Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])=[CH:9][C:8]=1[N+:27]([O-])=O)(=[O:3])[CH3:2].[H][H]>CO.COCCO.[Ni]>[C:1]([NH:4][C:5](=[O:30])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)(=[O:15])=[O:16])=[CH:9][C:8]=1[NH2:27])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: COCCO
Product: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N

Procedure:
59 g of 2-(3-acetylureido)-5-(3-trifluoromethylphenylsulfonyloxy)nitrobenzene in 200 ml of methanol and 200 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After hydrogen uptake is complete, the catalyst is filtered off with suction, washed with warm 2-methoxyethanol and the solution is evaporated under reduced pressure. Water is added to the residue and it is then filtered off with suction, washed with water and dried over sodium hydroxide, melting point 182° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH3:10])[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[OH-].[Na+]>O>[CH2:17]([O:16][C:14]([NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH3:10])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C[C@H](N)C(=O)O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a stirred solution of the 5,5,5-trifluoro-L-leucine (12 g) in H2O (150 mL) at 0° C. was added benzyl chloroformate (4.8 mL, 34 mol), followed by dropwise addition of 1 M aqueous NaOH (120 mL, 120 mmol). More benzyl chloroformate (4.8 mL, 34 mmol) was added. The mixture was further stirred at 0° C. and the pH of the mixture became ˜7. The mixture was washed with Et2O (2×) and acidified with aqeous HCl. The aqueous layer was extracted with EtOAc (3×), dried (Na2SO4) and concentrated in vacuo to provide N-[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucine. The crude acid was dissolved in Et2O and treated with a solution of diazomethane in Et2O. Chromatography over silica gel and elution with hexanes:Et2O (7:3) gave methyl (4S)-N-[(benzyloxy)carbonyl]-5,5,5-trifluoro-L-leucinate as the less polar fraction.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>ClCCl.O1CCCC1>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:8]3[CH:9]=[C:10]4[C:5]([CH2:4][CH2:3][CH2:2][O:1]4)=[CH:6][C:7]=3[OH:11])[C:25]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2c(c1)CCCO2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 500 mL round-bottom flask was charged with chroman-6-ol (9.2 g, 61 mmol) and tetrahydrofuran (120 mL). A 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (32.5 mL, 65.0 mmol) was added at 5° C. and the reaction mixture was stirred for 15 min and concentrated in vacuo. To the residue was added dichloromethane (180 mL), followed by a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (18.8 g, 60.0 mmol) in dichloromethane (180 mL) at 5° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 24 h. Saturated aqueous ammonium chloride (7 mL) was added and the reaction mixture was concentrated in vacuo. Trituration of the residue in methanol/water (1/100, 200 mL) afforded 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one. A mixture of the 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one, triethylsilane (23.2 g, 200 mmol), trifluoroacetic acid (50.0 g, 438 mmol) and dichloromethane (200 mL) was stirred at ambient temperature for 20 h and concentrated in vacuo. Trituration of the residue in diethyl ether (150 mL) afforded 1-(diphenylmethyl)-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one (24.3 g, 90%) as an off-white solid: MS (ES+) m/z 448.0 (M+1).
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1>N1C=CC=CC=1.C1C=CC=CC=1>[Cl:3][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1
Reactant: CC(CCCC1CCCCC1)c1ccc(CCCO)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(CCCC1CCCCC1)c1ccc(CCCCl)cc1

Procedure:
Next, 0.82 g of Li[AlH4 ] was added to 50 ml of dried (C2H5)2O, and the resulting mixture was stirred. Thereto was gradually added 5 g of 4-[p-(2-hydroxycarbonylethyl)phenyl]pentylcyclohexane. Thereafter the thus obtained mixture was stirred for 5 hours, and filtered. The (C2H5)2O was distilled off from the filtrate, and the residue was recrystallized from n--C6H14 to obtain 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C. To a mixture of 3.6 g of SOCl2, one drop of pyridine and 50 ml of benzene was added 4.3 g of the 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane obtained above, and the resulting mixture was refluxed for 5 hours. Thereafter, the surplus SOCl2 was distilled off to obtain 4-[p-(3-chloropropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][CH:6]=[CH:5]2.C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:21][C:10]1[C:11]([O:12][CH3:13])=[C:2]([CH3:1])[CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2ncccc2cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(C)cc2cccnc2c1Br
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of 6-methyl-7-methoxy-quinoline (3.0 g, 17.3 mmol) in DMF (20 ml) was added NBS (3.4 g, 19 mmol). The resulting suspension was stirred for 3 h at 60° C. and monitored by LCMS. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and then purified by flash column chromatography on silica gel to give the desired product (2.9 g, 67%). MS (ES) m/z 251.6 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][CH2:11][C:19]#[N:20]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCc1cccs1
Temperature: 90 °C

Procedure:
A mixture was prepared from 20.8 g of 2-[2-(4-toluenesulfonyloxy)ethyl]thiophene, 5.4 g of sodium cyanide and 175 ml of dimethylsulfoxide and this mixture was heated to 90° C. The mixture was quenched by pouring it into saturated aqueous ammonium chloride solution and the resulting solution was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give crude 2-thiophenepropionitrile. This product was mixed with 175 ml of 1M diborane in tetrahydrofuran and allowed to stir at room temperature. The reaction was quenched in ethanol and methanolic hydrogen chloride was added. The white solid which formed was separated by filtration, washed with ether and dried in a vacuum oven to give 3-(2-thienyl)propylamine hydrochloride melting at about 197°-198° C.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[CH:7][NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].C1C(=O)N([Br:18])C(=O)C1.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([Br:18])[NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1c(C)[nH]c(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3-acetyl-2,4-dimethyl-1H-pyrrole (2.89 g, 21.1 mmol) in THF (80 mL) was added NBS (3.75 g, 21.1 mmol) at −78° C. under nitrogen. After stirring for 30 minutes at same temperature, the mixture was allowed to warm to room temperature and stirred for 1 hour. Sodium sulfite (4.3 g) was added to the mixture and volatiles were removed by evaporation. Water (100 mL) was added to the mixture, and the precipitates were collected by filtration to give 5.33 g (quant. including water) of the subtitle product.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]#[N:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[OH-:29].[K+]>C(O)(C)(C)C.O>[O:28]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([NH2:26])=[O:29])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC#N)c2c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(CCC(N)=O)c2c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-propionitrile (150 mg, 0.38 mmol), and powdered potassium hydroxide (172 mg, 3.07 mmol) in tert-butanol (8 mL) was heated with stirring under reflux for 1.5 hours. After being cooled to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (eluting with 5% methanol in dichloromethane) to afford 125 mg of the product as a white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:59]C1C=CC=CC=1C(Cl)=O>>[Cl:59][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccccc1Cl
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4Cl)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 131 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2-chloro benzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:26]([OH:28])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:52][C:53]([F:64])([F:63])[O:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH2:60])=[CH:57][CH:56]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C@@H:10]([C:26](=[O:28])[NH:60][CH2:59][C:58]2[CH:61]=[CH:62][C:55]([O:54][C:53]([F:52])([F:63])[F:64])=[CH:56][CH:57]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C3CC3)cc2)[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C3CC3)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)cc2)C1
Yield: 55.3 %

Procedure:
To a solution of the compound (168 mg) obtained in Step 2 in N,N-dimethylformamide (1.7 ml) were successively added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (94 mg), 1-hydroxybenzotriazole hydrate (75 mg) and 4-trifluoromethoxybenzylamine (85 mg). After stirring overnight at room temperature, the mixture was partitioned by adding ethyl acetate, saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (132 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:13]=[C:14]([C:18]2[N:23]=[C:22]([CH3:24])[C:21]([C:25](Cl)=[O:26])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([NH2:41])[CH:36]=[CH:35]2)(=[O:31])=[O:30]>C1COCC1.N1C=CC=CC=1>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([NH:41][C:25]([C:21]1[C:22]([CH3:24])=[N:23][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=3)=[N:19][CH:20]=1)=[O:26])[CH:36]=[CH:35]2)(=[O:31])=[O:30]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Reactant: CS(=O)(=O)c1ccc2c(ccn2N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(S(C)(=O)=O)ccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
2.0 M of NaHMDS (sodium bis(trimethylsilyl)amide) in THF is added to a stirred solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (0.72 mmol) and 5-methanesulfonyl-indol-1-ylamine (0.72 mmol) and in anhydrous pyridine (10 mL) at rt. The reaction mixture is stirred at 90° C. overnight and then concentrated in vacuo. The residue is purified ny silica gel chromatography eluting with 1.5% MeOH in DCM to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methanesulfonyl-indol-1-yl)-amide (50 mg, 8%) as a solid. MS: 425 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.86 (s, 3H), 3.02 (s, 3H), 6.55 (s, H) 6.92 (d, H), 7.17-7.38 (m, 3H), 7.53 (m, H), 7.78 (s, H), 8.27 (d, H), 8.38 (d, H), 9.16 (s, H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[S:12][CH2:13][CH3:14].C([Li])CCC.CN(C)[CH:22]=[O:23]>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:13]([S:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:22]=[O:23])[CH:3]=2)[N:8]=[CH:7][CH:6]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCSc1ccnc2ccc(Br)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSc1ccnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 6-bromo-4-ethylsulfanyl-quinoline (1.48 g, 5.5 mmol) in THF (60 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (2.42 mL, 6.07 mmol, 1.1 equiv.) at −70° C. During the addition, the color of the solution was turned into a dark brown and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.848 mL, 11 mmol) in THF (5 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the yellow solid which was dissolved in ethyl acetate (−10 mL) at hot condition and diluted with hexanes (−20 mL). After cooling in the refrigerator overnight, the solids were collected by filtration and washed with 10% ethyl acetate in hexanes. After drying in air, 0.614 g (51% yield) of 4-ethylsulfanyl-quinoline-6-carbaldehyde was isolated as a yellow solid: EI-HRMS m/e calcd for C12H11NOS (M+) 217.0561, found 217.0554.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:27]1[CH:26]=[CH:25][C:24]([C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])=[CH:29][CH:28]=1)(=[O:5])=[O:4]
Reactant: O=C(c1ccc(O)cc1)N1CCOCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(OS(=O)(=O)C(F)(F)F)cc1)N1CCOCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1.23 ml (7.24 mmol) of trifluoromethanesulphonic anhydride are slowly added dropwise to a solution, cooled to −10° C., of 1.0 g (4.83 mmol) of 4-(4-morpholinylcarbonyl)phenol and 2.02 ml (14.48 mmol) of triethylamine in 20 ml of dichloromethane. The mixture is stirred at −10° C. for 30 min and then at 0° C. for 30 min. It is washed successively with 10% strength sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo, and the residue is dried under high vacuum. 1.71 g (94.6% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:30](=[O:31])[C:27]3[CH:28]=[CH:29][C:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(OC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-biphenylcarbonyl chloride (14 mg) and N,N-diisopropylethylamine (28 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.C(N(CC)CC)C.ClC(OCC)=O.[NH2:26][CH2:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([O:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:33][C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:42][CH:43]=1)=[O:8]
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)C=Cc2ccccc2Cl)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a mixture of 11.50 g. (63 mMol) o-chlorocinnamic acid, 200 ml. anhydrous tetrahydrofuran and 6.38 g. (63 mMol) anhydrous triethylamine, there are added dropwise at -15° C., 7.50 g. (69 mMol) ethyl chloroformate. The reaction mixture is then stirred for 15 minutes at -15° C. Subsequently, a solution of 15.80 g. (63 mMol) ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate in 50 ml. anhydrous tetrahydrofuran is added dropwise thereto and the reaction mixture is stirred for a further 2 hours at -10° C. and then left to stand for a day at ambient temperature. Thereafter, the tetrahydrofuran is distilled off in a vacuum and the residue is taken up in methylene chloride. The methylene chloride phase is extracted with 0.5 N aqueous sodium hydroxide solution, filtered, dried over anhydrous sodium sulphate and evaporated. After recrystallization of the residue from a mixture of ligroin and acetone (30:5 v/v), there is obtained, in a yield of 65% of theory, ethyl 2-{4-[2-(2-chlorocinnamoylamino)-ethyl]-phenoxy}-2-methylpropionate, which melts at 76° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH:9]=[CH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](Cl)=[O:27]>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:26](=[O:27])[N:25]([CH3:24])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:3][CH:4]=2)=[O:23])[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1cc(C=CC(=O)c2ccc(O)cc2)cc(OC)c1OC
Product: COc1cc(C=CC(=O)c2ccc(OC(=O)N(C)c3ccccc3)cc2)cc(OC)c1OC

Procedure:
The title product was prepared from 1-(4-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (82%, yellow solid). HPLC-MS: m/z=448.2 (M+1); Rt: 4.61 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:23])[C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:24][NH:25][CH3:26]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][N:25]([CH3:26])[CH3:24])[CH2:11][CH2:10]2)[CH3:23])=[N:6][CH:7]=1
Reactant: CNC
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1
Solvent: CO
Product: CN(C)CCC[C@H]1CC[C@H](N(C)c2ncc(Br)cn2)CC1
Temperature: 25 °C

Procedure:
A solution of 209 mg (corresponding to 0.50 mmol) of crude trans-Methanesulfonic acid 3-{4-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-propyl ester in 5 ml of methanol was treated with 0.89 ml (5 mmol) Dimethylamine (33% in EtOH, 5.6M) and stirred over night at RT. After the addition of 0.45 ml (2.5 mmol) Dimethylamine (33% in EtOH, 5.6M), the reaction was stirred for 66 h, then heated at 70° C. for 2 h, cooled, evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 97:3 to 94:6) gave 157 mg (88%) of trans-(5-Bromo-pyrimidin-2-yl)-[4-(3-dimethylamino-propyl)-cyclohexyl]-methyl-amine, MS: 355 (MH+, 1Br).
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=3[O:26][CH3:27])[C:13]=2[C:28]=1[CH3:29])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[C:13]3[C:28]([CH3:29])=[C:9]([NH2:8])[C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=3[O:16][CH2:15]2)=[C:18]([O:26][CH3:27])[CH:19]=1)([CH3:25])[CH3:24]
Reactant: COc1cc(C(C)C)ccc1C1COc2c(C)c(C)c(NCc3ccccc3)c(C)c21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C(C)C)ccc1C1COc2c(C)c(C)c(N)c(C)c21
Yield: 87 %

Procedure:
Using N-benzyl-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 273, the title compound was synthesized in the same manner as in Reference Example 30. Yield 87%. Melting point: 120-121° C. (ethyl acetate-hexane).