Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:9][C:10]([C:13]3[CH:18]=[C:17]([O:19][Si](C(C)C)(C(C)C)C(C)C)[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=3)=[CH:11][CH:12]=2)=[N:4]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:9][C:10]([C:13]3[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:14]=3)=[CH:11][CH:12]=2)=[N:4]1)[CH3:2]
Reactant: CC[C@@H]1COC(c2ccc(-c3cc(O[C@@H](C)COC)cc(O[Si](C(C)C)(C(C)C)C(C)C)c3)[nH]2)=N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@@H]1COC(c2ccc(-c3cc(O)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
(4R)-4-Ethyl-2-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazole (965 mg, 1.93 mmol) synthesized in Example (108a) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 2.50 mL, 2.50 mmol) was added at room temperature, followed by stirring at room temperature for 1 hour under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with methylene chloride (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-4%) to afford the desired compound (550 mg, yield 83%) as a white solid.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9](Cl)=[C:10]([CH3:16])[C:11]=2[CH3:15])[N:6]=1.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CO>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([CH3:16])[C:11]=2[CH3:15])[N:6]=1
Reactant: Sc1ccccc1
Reactant: Cc1c(Cl)nc2nc(N)ccc2c1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(Sc2ccccc2)nc2nc(N)ccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
13 g of a 30% strength methanolic sodium methylate solution is introduced into 5.0 g (24 mmol) of 2-amino-7-chloro-5,6-dimethyl-1,8-naphthyridine and 8.0 g (72 mmol) of thiophenol in 100 ml of anhydrous methanol. The mixture is boiled under reflux for 3 hours and stirred overnight at room temperature. 200 ml of water is added, the mixture is stirred for 1 hour, and the precipitated solid is filtered off, washed with a small amount of methanol and dried under reduced pressure. There is obtained 4.7 g of a pale yellow solid.
Reaction SMILES: [CH:1]([Si:4]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][CH2:17][OH:18])([CH3:3])[CH3:2].[C:25]([O:29][C:30](=[O:50])[CH2:31][C@H:32]([NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1O)(=[O:42])=[O:41])[C:33]([N:35]([O:37][CH3:38])[CH3:36])=[O:34])([CH3:28])([CH3:27])[CH3:26].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:25]([O:29][C:30](=[O:50])[CH2:31][CH:32]([NH:39][S:40]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=1[O:18][CH2:17][CH2:16][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:19]([CH3:21])[CH3:20])[CH:22]([CH3:24])[CH3:23])(=[O:42])=[O:41])[C:33]([N:35]([O:37][CH3:38])[CH3:36])=[O:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Reactant: CC(C)[Si](Oc1ccc2ccccc2c1CCO)(C(C)C)C(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCCc1c(O[Si](C(C)C)(C(C)C)C(C)C)ccc2ccccc12
Yield: 69.8 %

Procedure:
2-(2-Triisopropylsilanyloxy-naphthalen-1-yl)-ethanol (1.0 g, 2.91 mmol) was mixed with (S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (1.13 g, 2.91 mmol), diethylazodicarboxylate (0.92 mL, 5.8 mmol), and triphenyl phosphine (1.52 g, 5.82 mmol) in THF (18.6 mL) at room temperature for 16 h. The reaction mixture was concentrated onto SiO2 (˜3 g) and then was chromatographed over SiO2 with 20% EtOAc/hexane to give N-methoxy-N-methyl-3-{2-[2-(2-triisopropylsilanyloxy-naphthalen-1-yl)-ethoxy]-benzenesulfonylamino}-succinamic acid tert-butyl ester (1.45 g, 2.03 mmol) as an oil in 69% yield. MS (APCI) m/z 715.4 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:26])[CH:22]=2)[CH:17]1[CH2:27][C:28](OCC)=[O:29])[CH:13]([CH3:15])[CH3:14]>O>[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:26])[CH:22]=2)[CH:17]1[CH2:27][C:28]([NH:10][C:9]([NH2:11])=[NH:8])=[O:29])[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)CC1c2ccc(C)cc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)C(=O)N(CC(C)C)C2CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 40 h
Yield: 70.2 %

Procedure:
N-[(2-Isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 1.75 g of potassium tert-butoxide, 1.78 g of guanidinium chloride and 0.9 g of ethyl (2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 40 hours and is then poured into 150 cm3 of water and extracted with 3 times 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is taken up in diethyl ether and then filtered, giving 0.66 g of N-[(2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine in the form of a white solid melting at 266° C. (Analysis C16H22N4O2% calculated C, 63.56; H, 7.33; N, 18.53; O, 10.58%. found C, 63.57; H, 7.48; N, 18.50).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[I:14]Cl>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([I:14])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(Cl)cc21
Reactant: ClI
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(I)c(Cl)cc21
Yield: 38.6 %

Procedure:
1-Acetyl-6-chloroindoline (0.3 g, 1.53 mmol) and iodine monochloride (2.48 g, 15.3 mmol) in acetic acid (25 ml) were heated under reflux for 48 hours. After cooling the mixture was partitioned between ethyl acetate and 10% aqueous NaOH. The organic extract was washed with aqueous Na2 SO3 dried (Na2SO4) & evaporated to dryness under reduced pressure. Chromatography on silica gel using dichloromethane afforded the title compound (0.19 g, 39%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:20]1[CH:21]=[N:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=1>N1C=CC=CC=1.[Cu]Br>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[CH:21]=[N:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: N#Cc1ncc(Br)cn1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1ncc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 0 °C

Procedure:
3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) (1.81 g, 8.33 mmol) was dissolved in pyridine (40 ml) and sodium hydride (60% in mineral oil, 0.40 g, 10.0 mmol) was added with stirring under argon at 0° C. The mixture was left to stir for 5 minutes. Copper (I) bromide (1.68 g, 11.7 mmol) was added and the mixture allowed to warm to room temperature over 30 minutes. 5-Bromo-2-pyrimidinecarbonitrile (D38) (2.30 g, 12.5 mmol) in pyridine (8 ml) was added and the mixture heated at 100° C. for 1 hour. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The crude product was purified by column chromatography, eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (E177a); MS (ES+) m/e 321 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CCN(CC)CC.[CH3:28][C:29](OC(C)=O)=[O:30]>C(Cl)Cl>[C:29]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:16]1[CH2:15][O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:30])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(OC[C@H]2CCCN2)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC[C@@H]1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(2R)-2-(((3-nitro-5-(trifluoromethyl)phenyl)oxy)methyl)pyrrolidine (3.46 g, 11.9 mmols, 1 eq) was dissolved in 100 mL of CH2Cl2. Et3N (5 mL, 35.7 mmols, 3 eq) was added followed by Ac2O (1.2 mL, 13.1 mmols, 1.1 eq). The reaction was stirred at RT for 1.5 h. The solvent was removed in vacuo and the residue dissolved in EtOAc. The solution was washed once each with saturated NH4Cl, 1 N HCl, and twice with brine. The organic layer was dried over Na2SO4 filtered and concentrated in vacuo. The crude material was purified on a Biotage chromatography system eluting with a gradient of 10% to 75% EtOAc:hexane to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1>C(O)(=O)C>[CH3:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([N:14]3[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]3)(=[O:19])=[O:18])[CH:21]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2cccc(S(=O)(=O)N3CCN(C)CC3)c2)nc1N
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine (0.50 g, 2.0 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130° C. for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to ˜9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2×30 mL) and the organic layer separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product (˜0.42 g) used in the next step without purification. MS (ES+): m/z 363 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCC=CCCc1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC=CCCc2ccc(OCc3ccccc3)cc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
8-(4-Benzyloxyphenyl)-5-octenol (24 g.) was added in portions over a 15 minute period to a solution of 19.5 g. of p-toluenesulfonyl chloride in 600 ml. of dry pyridine at -10° C. The reaction mixture was stirred for one hour at -10° C., then poured into ice-water and stirred for 20 minutes. The mixture was extracted with chloroform, and the latter washed with aqueous hydrochloric acid, aqueous sodium hydroxide, dried and concentrated. The resulting 8-(4-benzyloxyphenyl)-5-octenyl p-toluenesulfonate was used directly in the next reaction without further purification.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]([CH3:16])=[N:14][C:13]2[C:8](=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[NH:28][C:29]2[CH2:30][CH2:31][CH2:32][C:33](=[O:36])[C:34]=2[CH:35]=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]1[C:15]([CH3:16])=[N:14][C:13]2[C:8]([N:7]=1)=[C:9]([C:27]1[NH:28][C:29]3[CH2:30][CH2:31][CH2:32][C:33](=[O:36])[C:34]=3[CH:35]=1)[CH:10]=[CH:11][CH:12]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCCc2[nH]c(Br)cc21
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCCC4=O)c2nc1NC(C)(C)C
Temperature: 105 °C
Yield: 77 %

Procedure:
A mixture of N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b) (222.6 mg, 0.652 mmol), 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (303a; 209 mg, 0.978 mmol), K2PO4 (415 mg, 1.957 mmol), (Strem Chemicals, Inc., 31.1 mg, 0.065 mmol), and Pd2dba3 (Aldrich, 29.9 mg, 0.033 mmol) in a mixture of dioxane (4.5 mL) and water (0.900 mL) was heated under argon at 105° C. for 1 h. The reaction mixture was subsequently cooled to RT and diluted with water (30 mL). The resulting mixture was extracted with 5% MeOH/DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes) furnished 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-indol-4(5H)-one (175 mg, 0.502 mmol, 77% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.52 (1H, br. s.), 7.96 (1H, dd, J=7.6, 1.0 Hz), 7.73 (1H, d, J=7.8 Hz), 7.40 (1H, t, J=7.8 Hz), 7.08 (1H, d, J=2.0 Hz), 4.89 (1H, s), 2.93 (2H, t, J=6.2 Hz), 2.60 (3H, s), 2.51-2.57 (2H, m), 2.23 (2H, quin, J=6.3 Hz), 1.68 (9H, s). m/z (ESI, +ve) 349.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Cl:17]>>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCCBr
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OCCCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 1-(3-hydroxyphenyl)ethanone and 1-bromo-5-chloropentane.
Reaction SMILES: C([NH:4][C:5]1[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:14])(=O)C.[OH-].[NH4+]>O.C(O)C.Cl.S(=O)(=O)(O)O>[CH3:14][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[C:5]=1[NH2:4]
Reactant: CC(=O)Nc1c(C)cccc1C(C)=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cccc(C)c1N
Yield: 83 %

Procedure:
N-Acetyl-2-methyl-6-acetylaniline (76.1 g) in water (300 ml), ethanol (300 ml), concentrated hydrochloric acid (300 ml) and concentrated sulfuric acid (15 ml) were refluxed for 24 hours. The solution was cooled and concentrated ammonium hydroxide was added to pH 10. The solution was extracted with dichloromethane. The extracts were dried (MgSO4) and stripped. 2-methyl-6-acetylaniline (49.3 g) was obtained as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)N1CCN(C)CC1

Procedure:
4-Bromo-2-methylbenzoic acid (10 g, 46.5 mmol), and HBTU (23 g, 60.5 mmol) were dissolved in DMF (150 mL), then N-methyl piperazine (6.0 g, 60.5 mmol) and DIPEA (21 mL, 121 mmol) were added. The reaction was stirred overnight before the removal of the DMF in vacuo, the gum was quenched with 2.0N NaOH (100 mL), extracted with diethyl ether (3×200 mL), dried (MgSO4) and solvent removed in vacuo to yield a viscous gum. Purification on silica using 0-10% MeOH in DCM as eluent, gave the title compound as viscous oil. The oil was dissolved in the minimum amount of diethyl ether, iso-hexane was added to give a colourless solid which was filtered and dried (11.8 g, 86%); 1H NMR (CDCl3) 7.40 (s, 1H), 7.36 (d, 1H), 7.04 (d, 1H), 3.86-3.79 (m, 2H), 3.27-3.21 (m, 2H), 2.51-2.45 (m, 2H), 2.32-2.29 (m, 8H); MH+ 298.
Reaction SMILES: [CH:1]([N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2Br)[C@H:16]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[OH:33])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]2[O:33][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@H:17]3[CH2:18][N:14]([CH:1]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:15][C@@H:16]3[C:26]=2[CH:31]=1
Reactant: Oc1ccc(Cl)cc1[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H]1c1ccccc1Br
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)[C@H]1CN(C(c3ccccc3)c3ccccc3)C[C@@H]1c1ccccc1O2

Procedure:
A mixture of trans-2-(1-benzhydryl-4-(2-bromophenyl)pyrrolidin-3-yl)-4-chlorophenol (1.0 g, 1.93 mmol), cesium carbonate (1.26 g, 3.85 mmol, 2.0 eq.), N,N-dimethylglycine (79.5 mg, 0.77 mmol, 0.4 eq.) and CuI (147 mg, 0.77 mmol, 0.4 eq.) in dioxane (10 ml) was heated to reflux overnight while stirring under inert nitrogen atmosphere. The reaction mixture was filtered over Celite on a glass filter. The residual solids were washed with dioxane (15 ml). The combined filtrates were concentrated under vacuum to give the title compound as an oil, 0.9 g in quantitative yield. The purity according to LC-MS was 72%. The product was used without further purification. MS: M+1=437, 439 found. 1H-NMR (CDCl3) δ (ppm) 3.01-3.20 4H, m; 3.65 2H, m; 4.61 1H, m; 6.93-7.55 17H, m, ArH.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH2:13][O:14][CH3:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COc1ccc(Br)c(O)c1
Reactant: COCCBr
Product: COCCOc1cc(OC)ccc1Br

Procedure:
Starting from commercially available 2-bromo-5-methoxy-phenol and 1-bromo-2-methoxy-ethane the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[F:12][C:13]1[CH:14]=[N:15][C:16]([C@@H:19]([NH2:21])[CH3:20])=[N:17][CH:18]=1.[F-].[Cs+]>CS(C)=O>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:21][C@H:19]([C:16]3[N:17]=[CH:18][C:13]([F:12])=[CH:14][N:15]=3)[CH3:20])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: C[C@H](Nc1ccc2ncc(Br)n2n1)c1ncc(F)cn1
Temperature: 180 °C
Yield: 64 %

Procedure:
A mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (Preparation 1b, 0.2 g, 0.86 mmol), (1S)-1-(5-fluoropyrimidin-2-yl)ethanamine (prepared according to the method described in WO2006/82392A1, 0.24 g, 1.72 mmol), cesium fluoride (1.31 g, 8.60 mmol) and dimethylsulfoxide (5 mL) was heated at 180° C. for 2 hours in a sealed tube. The reaction was cooled down, filtered through Celite® eluting with ethyl acetate and the filtrate was washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (40-70% acetone in hexanes) to give the title compound (0.11 g, 64%) as a brown foam.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 13.5 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=2)[O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[O:26][C:25]([C:27]([O:29]CC)=O)=[N:24][N:23]=3)[CH:17]=2)=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].[NH4+:40].[OH-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=2)[O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[O:26][C:25]([C:27]([NH2:40])=[O:29])=[N:24][N:23]=3)[CH:17]=2)=[CH:4][C:3]=1[C:36]([F:38])([F:37])[F:39]
Reactant: CCOC(=O)c1nnc(-c2cc(Oc3cccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)ccn2)o1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1nnc(-c2cc(Oc3cccc(CCC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)ccn2)o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl 5-{4-[3-(3-{[4-chloro-3-(trifluoromethyl)phenyl]-amino}-3-oxopropyl)phenoxy]pyridin-2-yl}-1,3,4-oxadiazole-2-carboxylate (100 mg) in NH4OH (10 mL) was allowed to stir at rt for 90 min. The reaction mixture was concentrated and the residue recrystallized from MeOH to give A-102. 1H NMR (300 MHz, d6-DMSO) δ: 8.70 (br s, 1H), 8.62 (d, 1H), 8.29 (br s, 1H), 8.13 (d, 1H), 7.76 (dd, 1H), 7.58-7.64 (m, 2H), 7.45 (t, 1H), 7.23-7.28 (m, 1H), 7.14-7.19 (m, 2H), 7.07-7.13 (m, 1H), 2.97 (t, 2H), and 2.69 (t, 2H). LCMS, FA: Rt=1.77 min, [MH+ 532.1].
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[C:30](O)(=[O:32])[CH3:31]>>[C:30]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CC(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with acetic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-acetyl-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 408 (M+H)+.