Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@@H:19]([OH:23])[CH:20]([CH3:22])[CH3:21])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:45]1(C)[CH:50]=CC(S(O)(=O)=O)=C[CH:46]=1.C(=O)(O)[O-].[Na+]>COC(OC)(C)C>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]1[C@H:19]([CH:20]([CH3:21])[CH3:22])[O:23][C:45]([CH3:50])([CH3:46])[O:24]1)=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)OC
Product: CC(C)[C@@H]1OC(C)(C)O[C@@H]1[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C

Procedure:
50 mg of (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylpentyl]imidazole-4-propionamide and 50 mg of p-toluenesulphonic acid in 3 ml of dimethoxypropane are stirred at room temperature overnight. The reaction mixture is thereafter poured into 2N sodium bicarbonate solution and extracted with ethyl acetate. The organic phases are washed with water, dried and evaporated, whereby there is obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(S)-(cyclohexylmethyl)[(4R,5S)-5-isopropyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]imidazole-4-propionamide as a solid, MS: 673 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([Cl:34])(=[O:33])[CH3:32]>CN(C=O)C>[ClH:34].[C:31]([NH:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.12 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzo-thiophene-2-carboxamide dihydrochloride are initially charged in 0.3 ml of DMF, and 18.7 mg (0.18 mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added. After 16 h of stirring at RT, a further 18.7 mg (0.18 mmol) of triethylamine and 11.6 mg (0.15 mmol) of acetyl chloride are added. After a further 12 h of stirring at RT, the supernatant solution of the reaction mixture is purified by preparative HPLC. The product fractions are concentrated and the residue is dissolved in a mixture of methanol and 4M HCl in dioxane, then reconcentrated and dried under high vacuum. 8 mg (17.1% of theory) of the title compound are obtained.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CCC(=O)C.O>[C:14]1([S:20]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=3[CH:3]=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
A mixture of methyl indole-4-carboxylate (J. Org. Chem. 1980, 45, 3350) (5.0 g, 28.5 mmol), benzenesulphonyl chloride (10.1 g, 57.1 mmol) and anhydrous potassium carbonate (15.78 g, 114 mmol) in butan-3-one (150 ml) was refluxed under nitrogen for 15 hours. Additional benzenesulphonyl chloride (10.1 g) and anhydrous potassium carbonate (10.1 g) were added and refluxing was continued for 5 hours. The mixture was diluted with water (300 ml) and extracted with diethyl ether (3×300 ml). The combined organic solutions were dried (MgSO4) and concentrated to give a white solid which was recrystallised from ethanol (6.35 g, 72%); δH (360 MHz, CDCl3), 8.21 (1H, d, J=8.3 Hz, Ar—H), 7.96 (1H, dd, J=8.1 and 0.7 Hz, Ar—H), 7.87-7.84 (2H, m, Ar—H), 7.69 (1H, d, J=3.7 Hz, Ar—H), 7.56-7.33 (5H, m, Ar—H), 3.94 (3H, s, —OMe); m/z (CI) 316 (M++1).
Reaction SMILES: [NH2:1][C:2]([C:14]1[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)=[N:16][C:17]([S:21][CH3:22])=[N:18][C:19]=1[NH2:20])=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6]CC)=O.CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:16][C:17]([S:21][CH3:22])=[N:18][C:19]=2[N:20]=[C:4]([OH:6])[C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C(=O)OCC)=C(N)c1c(N)nc(SC)nc1-c1cccc([N+](=O)[O-])c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCCC
Product: CCOC(=O)c1c(O)nc2nc(SC)nc(-c3cccc([N+](=O)[O-])c3)c2c1N
Temperature: 240 °C

Procedure:
A suspension of diethyl 2-(amino-[6-amino-2-methylthio-4-(3-nitrophenyl)-pyrimidin-5-yl]-methylene)-malonate (example 30b, 1.34 g) in diphenyl ether (30 ml) was heated under a stream of nitrogen to 240° C. for 2 h. After the mixture was cooled to room temperature, heptane was added (200 ml) and the solids were collected by filtration. The title compound was purified by chromatography on silica gel using CH2Cl2/acetone=1/0 to 4/1 (v/v) as eluent.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[N:6]=1)=O.[OH-].[NH4+:15]>>[N:13]1[CH:12]=[CH:11][N:8]2[CH:9]=[CH:10][C:5]([C:3]([NH2:15])=[O:2])=[N:6][C:7]=12
Reactant: [NH4+]
Reactant: COC(=O)c1ccn2ccnc2n1
Agent: [OH-]
Product: NC(=O)c1ccn2ccnc2n1
Temperature: 100 °C
Yield: 58 %

Procedure:
A mixture of imidazo[1,2-α]pyrimidine-7-carboxylic acid methyl ester (580 mg) and 28% ammonium hydroxide was heated at 100° C. in a sealed tube for 2 h then cooled to ambient temperature. The resulting solid was filtered, washed with ice-cold water and dried under vacuum to give imidazo[1,2-α]pyrimidine-7-carboxylic acid amide (310 mg, 58%) as a white solid: δH (360 MHz, DMSO) 7.61 (1H, d, J 7), 7.77 (1H, s), 7.92 (1H, d, J 1), 8.09 (1H, d, J 1), 8.32 (1H, s), 9.11 (1H, d, J 7).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].O.C([O-])([O-])=O.[K+].[K+].CO[CH2:28][CH2:29]OC>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:28]=[CH2:29])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (6 g, 17.7 mmol) in DME (100 mL) was added Pd(Ph3)4 (1.0 g, 0.9 mmol) under argon atmosphere and the mixture was stirred for 30 min at ambient temperature. After addition of vinyl boronic anhydride pyridine complex (4.3 g, 17.7 mmol), water (25 mL) and K2CO3 (2.45 g, 17.7 mmol) the reaction was heated under reflux for 7 h. The reaction mixture was concentrated in vacuo to half of the volume, quenched by addition of saturated aqueous NaHCO3 and extracted with EtOAc. After drying (Na2SO4) the solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (eluent: hexane/EtOAc 9:1 to 4:1) to afford the title compound as a colorless oil. 1H-NMR (500 MHz, DMSO): δ (ppm) 7.62 (d, 1H), 7.45 (m, 1H, —NH), 7.35 (d, 1H), 6.68 (dd, 1H), 5.82 (d, 1H), 5.32 (d, 1H), 4.18 (d, 2H), 1.39 (s, 9H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[NH:4][CH:3]=1.[OH-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:3]=1
Reactant: COc1ccnc2[nH]cc(I)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
A solution of 3-iodo-4-methoxy-1H-pyrrolo[2,3-b]pyridine (0.30 g, 1.08 mmol) in dimethylformamide (10 mL) at 0° C. was treated with sodium hydroxide (0.056 g, 1.41 mmol) for 15 minutes. To the material was added benzenesulfonyl chloride (0.25 g, 1.41 mmol) dropwise and stirred at room temperature for 3 hours. The material was diluted with water (40 mL), filtered, and dried in vacuo at 50° C. to afford 0.35 g of the title compound. MS (ESI) m/z 414.9 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:19])[C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1ccnc(Nc2ccc(I)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccnc(N(C)c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and 2-chloro-4-methoxypyrimidine (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg). (2) Under an argon atmosphere, N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg) was added to a suspension of sodium hydride (11 mg) in anhydrous DMF (5 ml), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.0096 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=3/1) to obtain N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (46 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9](Cl)=[O:10])(=[O:6])=[O:5].[CH:12]([S:14][CH2:15][CH2:16][NH2:17])=[CH2:13].C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([NH:17][CH2:16][CH2:15][S:14][CH:12]=[CH2:13])=[O:10])(=[O:6])=[O:5]
Reactant: O=C(Cl)CCS(=O)(=O)CCCl
Reactant: C=CSCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CSCCNC(=O)CCS(=O)(=O)CCCl
Reaction time: 2 h

Procedure:
A solution of 5.92 g 3-(2-chloroethylsulphonyl)-propionyl chloride in 75 ml dichloromethane was treated dropwise with a solution of 2.65 g 2-vinylthioethylamine and 2.6 g triethylamine in dichlormethane. After 2 hours, the solution was evaporated and the residue recrystallised from aqueous ethanol. Yield 6.1 g; Mp. 102° to 103° C.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].COC(C)(C)C>O>[OH:14][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: O=C(O)[C@@H](O)Cc1ccccc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of 8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of water and then, at an inside temperature of 20° C., a mixture of 10.45 g (151.5 mmol) of sodium nitrite and 20 g of water was added over 5 hours. After addition, the mixture was stirred at 20° C. for 20 hours, 100 ml of t-butyl methyl ether was then added and, after 30 minutes of stirring at 20° C., the organic phase was separated (extract 1). Further, 50 ml of t-butyl methyl ether was added to the aqueous phase, the mixture was stirred at 20° C. for 30 minutes, and the organic phase was separated (extract 2). The extracts 1 and 2 were combined. The combined extract (116.5 g) contained 8.6 g of (2S)-2-hydroxy-3-phenylpropionic acid (yield 86%, optical purity 95.9% ee). The proton concentration (normality) in the reaction of this example was 1.7 mol/kg, the amount of the protonic acid was 3.0 equivalents (relative to L-phenylalanine), and the reaction temperature was 20° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[O:35]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:45]2[CH:46]=[CH:47][C:42]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:43][CH:44]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1ccc(NCc2cccc3ccccc23)cc1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1ccc(NCc2cccc3ccccc23)cc1
Temperature: 80 °C
Yield: 33.3 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{4-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (273 mg, 0.53 mmol), Pd (PPh3)4 (96 mg, 0.11 mmol), and 4-phenoxyphenylboronic acid (226 mg, 1.1 mmol) were dissolved in 5 mL of toluene, a 1M Na2CO3 solution (1.3 mL, 1.3 mmol) added and the mixture heated at 80° C. for 16 h. The reaction mixture was evaporated to dryness and the crude mixture purified over silica gel (8:2, DCM-hexanes) to give (S)-2-{4-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (107 mg).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH3:17][C:18](=[O:21])[C:19]#[CH:20].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][CH:20]=[C:19]([C:18](=[O:21])[CH3:17])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C#CC(C)=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (9.76 g, 0.041 mol) in CH2Cl2 (40 mL) at 0° C., was added dropwise over a 5 minutes period but-3-yn-2-one (2.0 g, 0.029 mol) followed by trifluoroacetic acid (0.22 mL, 0.003 mol) (very exothermic reaction). The ice bath was removed after 30 minutes, and the solution was stirred at 25° C. for an additional 2 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/Heptane 1:1) afforded 2.90 g (49%) of the title compound as a yellow oil. ES-MS m/e: 202.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Na].[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])(=[O:28])[CH2:26][CH3:27]>C1C=CC=CC=1>[C:25]([CH:29]([C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17])[C:30]([O:32][CH3:33])=[O:31])(=[O:28])[CH2:26][CH3:27]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: CCC(=O)CC(=O)OC
Agent: [Na]
Solvent: c1ccccc1
Product: CCC(=O)C(C(=O)OC)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Following the procedure of Example 1, 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid chloride is added to the sodium salt of methyl propionylacetate in benzene to give methyl 2-propionyl-4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (cpd. 16 in Table A). This pentanoate is then heated with DMSO and NaCl to give 2-[4-(4-trifluoromethylphenoxy)phenoxy]-3,5-heptanedione (cpd. 16, Table B).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Anisole (2.16 g, 20 mmol) was dissolved in toluene (20 ml). The mixture was cooled to −10° C. and aluminum chloride (2.67 g, 20 mmol) was added. 4-Chlorobutyryl chloride (2.47 ml, 22 mmol) was added dropwise at −10° C. and stirred for 0.5 hour at −10° C. The reaction mixture was poured into iced water (40 ml). After separation, the organic layer was washed with 20%citric acid (10 ml) twice, 1N-sodium hydroxide (10 ml) and 20% brine (10 ml) twice, and was concentrated under reduced pressure to give 4-chloro-1-(4-methoxyphenyl)-1-butanone (4.21 g, yield 99%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: COc1cccc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 85 mg (0.561 mmol) of 3-methoxybenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.45, FD-MS: M+ =561.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35]3)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:34]6[C:38](=[CH:39][CH:40]=5)[NH:37][C:36](=[O:41])[CH2:35]6)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc5c(c4)CC(=O)N5)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (Combi-Blocks, San Diego, USA, 35 mg, 0.128 mmol) to give the title compound as an off-white solid. (HPLC: tR 2.40 min (Method A); M+H=425 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 10.52 (s, 1H), 8.92 (s, 1H), 8.17 (s, 1H), 8.05-8.03 (m, 1H), 7.86-7.83 (m, 1H), 7.46 (s, 1H), 7.33-7.29 (m, 2H), 6.90-6.88 (m, 1H), 3.94 (s, 3H), 3.57 (s, 3H), 3.54 (s, 2H), 1.93 (s, 3H))
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].O1CCC[CH2:14]1.C[Al](C)C.[Cl-].[NH4+]>CCOC(C)=O.CCOC(C)=O.CCCCCC>[F:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]([CH3:14])=[N:11][CH:10]=1
Reactant: COC(=O)c1cc(Br)ncc1F
Reactant: C1CCOC1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(C)ncc1F
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-bromo-5-fluoroisonicotinate (1.0 g, 4.27 mmol) in tetrahydrofuran (25 ml) tetrakis(triphenylphosphine)palladium (495.0 mg, 0.43 mmol) was added. The mixture was stirred for 10 min, and then trimethylaluminum (5.13 ml, 1.00 M in heptane, 5.13 mmol) was added. The mixture was refluxed for 4 h, and the reaction was monitored by TLC (10% EtOAc-Hexane). Then, the reaction was diluted with EtOAc (75 ml) and a few drops of saturated. ammonium chloride were added.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[S:5][C:6]=1[Cl:7].[CH3:33]B(O)O.O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:7][C:6]1[S:5][C:4]([C:8]2[C:17]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:3][C:2]=1[CH3:33]
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cc(Br)c(Cl)s3)c2cc1OC
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cc(C)c(Cl)s3)c2cc1OC
Temperature: 100 °C
Reaction time: 96 h
Yield: 76 %

Procedure:
4-[2-(4-Bromo-5-chloro-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline (20 mg) was dissolved in dioxane (3 ml) to prepare a solution. Tetrakistriphenylphosphine palladium (25 mg), methylboronic acid (0.1 ml), water (0.3 ml), and cesium carbonate (182 mg) were added to the solution, and the mixture was stirred at 100° C. for 4 days. The reaction solution was filtered, and the solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (13 mg, yield 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[Na+].[I-:16].Cl.N>O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([I:16])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: [I-]
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Clc1ccc(-c2ccc(I)nn2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
20 ml ACN are added to 0.50 g (1.11 mmol) 3-(4-chlorophenyl)-6-chloropyridazine and 3.33 g (22.2 mmol) NaI before 189 μl fuming conc. HCl are added and the mixture is stirred at 80° C. for 4 h. The mixture is alkalised with aq. Ammonia solution (32%) diluted with water and extracted with EtOAc. The org. phases are combined, dried with Na2SO4 and the solvent is removed in vacuo. The resulting crude product is triturated with TBME.