Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.Cl[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[CH2:10]([SH:13])[CH2:11][CH3:12].[OH-].[K+]>C(Cl)Cl.CO>[C:7]([C:6]1([S:13][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5]1)(=[O:9])[CH3:8]
Reactant: CC(=O)CCCCl
Reactant: CCCS
Agent: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCSC1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
A solution of 134 g (0.83 mol) of bromine in 130 ml of methylene chloride is added dropwise at 10° C. with stirring to a solution of 100 g (0.83 mol) of 5-chloropentan-2-one in 400 ml of methylene chloride. The reaction mixture is stirred for a further hour at room temperature, then washed using water and dilute aqueous sodium carbonate solution and dried over sodium sulphate. The mixture is concentrated by stripping off the solvent under reduced pressure, and the residue is taken up in 200 ml of methanol and 63 g (0.83 mol) of n-propylmercaptan are added at 5° C. with stirring. A mixture of 93 g of potassium hydroxide powder in b 500 ml of methanol is then added dropwise. The reaction mixture is initially stirred for 2 hours at room temperature and then for 4 hours at 40° C. The mixture is then concentrated by stripping off the solvent under reduced pressure and the remaining residue is taken up in methylene chloride. The organic solution is washed successively using water, dilute aqueous sodium hydroxide solution and again using water, then concentrated under reduced pressure and then subjected to a vacuum distillation. In this manner, 42 g (32% of theory) of 1-acetyl-1-propylmercaptocyclopropane of boiling point 107° C./20 mbar are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:17][S:18]([O:9][CH2:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[CH3:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCCCC1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCCCC1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-methyl-2-piperidine-methanol (Aldrich, 0.27 mL, 2.1 mmol) in 10 mL tetrahydrofuran (THF) at 0° C. was added triethylamine (0.87 mL, 6.22 mmol) followed by methanesulfonyl chloride (0.24 mL, 3.1 mmol). The mixture was stirred at 0° C. for 10 min then the ice-bath was removed and the reaction mixture was stirred at 23° C. for an additional 1.5 h. The reaction mixture was filtered though Celite with THF and concentrated under reduced pressure. This crude material was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]3[CH2:17][CH2:16]3)([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: N#CC1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: N#C[C@@]1(C2CC2)CCN(c2ccnc(Cl)n2)C1=O

Procedure:
1-(2-Cloropyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile (23 g) obtained in Step D of Example 103 was resolved by HPLC (column: CHIRALPAK IC, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=200/800) to give the title compound (12 g: a shorter retention time).
Reaction SMILES: [C:1]([C:6]1[C:7]([Cl:19])=[C:8]([Cl:18])[C:9]2[O:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]=2[CH:17]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[CH3:21]NC.C=O>C(O)(=O)C.CN(C)C=O>[Cl:19][C:7]1[C:6]([C:1](=[O:5])[C:2](=[CH2:21])[CH2:3][CH3:4])=[CH:17][C:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=2[C:8]=1[Cl:18]
Reactant: CNC
Reactant: CCCC(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A stirred mixture of 5-butyryl-6,7-dichloro-2,3-dihydro-2-benzofurancarboxylic acid (12.0 g, 0.04 mole), dimethylamine hydrochloride (4.3 g, 0.052 mole), para-formaldehyde (1.9 g, 0.063 mole) and acetic acid (4 drops) was heated on a steam bath for 21/2 hours. Dimethylformamide (35 ml) was added and heating was continued for 11/2 hours. The reaction mixture was poured into ice water, extracted with ether, washed with water and dried over magnesium sulfate. The ether was evaporated in vacuo and the residue triturated with butyl chloride (100 ml) to give 9.0 g of 6,7-dichloro-2,3-dihydro-5-(2-methylenebutyryl)-2-benzofurancarboxylic acid which melted at 148° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:21][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CCCC1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
A mixture of 3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (57 mg, 0.2 mmol), 4-trifluoromethyl-benzoic acid (42 mg, 0.22 mmol), HATU (91 mg, 0.24 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 15 min. The crude was purified by HPLC to give the title compound (65 mg, 71%) as a brown solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 1.73-1.76 (m, 2H), 1.87-1.92 (m, 2H), 2.85-2.90 (m, 2H), 3.29-3.32 (m, 2H), 3.53-3.57 (m, 2H), 3.69 (s, 3H), 4.32 (t, J=4.80 Hz, 2H), 6.32 (d, J=2.02 Hz, 1H), 7.26 (d, J=8.59 Hz, 1H), 7.50 (d, J=1.78 Hz, 1H), 7.75 (d, J=2.53 Hz, 1H), 7.88-7.94 (m, 3H), 8.15 (d, J=8.84 Hz, 2H), 9.81 (s, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O2 458.2. found 459.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.[OH-].[NH4+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:19])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
3-Bromo-5-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (50 mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 μL), and the mixture stirred overnight. The solvents were pumped off. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for thirty min. The phases were separated and the organic layer was washed 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.57 min (ret time); analytical HPLC shows 96.5% purity, (ret time 12.131 min).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[Cl:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([Cl:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1Cl
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1Cl
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-5-chloro-3-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 160 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 20 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 50 mg of the title compound as a colorless powder.
Reaction SMILES: C([C:4]1([OH:16])[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH2:5]1)C=C.N[C@H:18]([C:27](O)=O)[CH2:19]C1C=CC(O)=CC=1.C(Br)C=C>>[CH2:27]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:16])=[CH:15][CH:14]=1)[CH:18]=[CH2:19]
Reactant: C=CCC1(O)C=CC(C[C@H](N)C(=O)O)=CC1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: C=CCBr
Product: C=CCN[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The compound of Formula II, 4-allyl-L-tyrosine, is synthesized according to the scheme set forth in FIG. 13. A protected tyrosine, e.g., an Nboc or Fmoc protected tyrosine, is reacted with allyl bromide, resulting in a protected allyl tyrosine, which is then typically deprotected to yield 4-allyl-L-tyrosine. For example, N-(tert-Butoxycarbonyl)-L-tyrosine (2.95 g, 10 mmole) was dissolved in 80 ml of DMF. The solution was chilled to 5° C. and NaH (0.63 g, 26 mmole) was added. The reaction mixture was allowed to warm up to 10° C. and stirred for additional 2 hours. After that, allyl bromide (1.33 g, 11 mmole) was added to the mixture and reaction was warmed to room temperature. The reaction mixture was stirred for 4 hours. Water was added to work up the reaction. The aqueous layer was extracted with ethyl acetate and CH2Cl2. The organic layer was dried over anhydrous MgSO4. The organic solvent was removed to give white solid. This compound was then refluxed in 4M HCl in 1.4-dioxane for 4 hours. All the solvent was evaporated to give the desired product as white solid (1.9 g, 86%). 1HNMR (CD3OD): d ppm 3.1 (m, 2H), 4.1 (t, 1H), 4.5 (d, 2H), 5.3 (q, 1H), 5.9 (m, 1H), 6.9 (d, 2H), 7.1 (d, 2H). Calculated molecular weight: 221, obtained molecular weight: 222.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([C:11]([F:13])([F:14])[F:12])=[CH:6][C:5]=1[NH:15][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (42.0 g, 122 mmol) in toluene (400 mL) was treated with acetic anhydride (12.8 mL, 135 mmol) and the mixture was heated to reflux for 16 h under nitrogen. It was then allowed to cool to r.t. and diluted with water. The mixture was rendered neutral by adding small portions of sodium hydrogencarbonate, and the organic layer was separated. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized in hexanes to give 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (43.4 g, 112 mmol, 92%) as a white powder, m.p. 96-98° C., ESI-MS: m/z 388 [M+H]+.
Reaction SMILES: ClCCl.[CH2:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([CH:14]=[CH:15][CH2:16][OH:17])=[CH:12][CH:11]=1)[CH3:5].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>C([O-])(=O)C.[Na+].CCCCCC>[C:23]([O:17][CH2:16][CH:15]=[CH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:4][CH3:5])=[CH:19][CH:18]=1)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: CCOCCOc1ccc(C=CCO)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOCCOc1ccc(C=CCOC(=O)CC(C)=O)cc1
Yield: 90.7 %

Procedure:
36 Milliliters of dichloromethane was added to 12 g of 4-[(1-ethoxy)ethoxy]cinnamyl alcohol, then 60 mg of anhydrous sodium acetate was added thereto. Under refluxing condition, 5 g of diketene was added dropwise to the reaction mixture, and 2 hours later, 0.42 g diketene was further added thereto, the whole reaction mixture was refluxed for 1.5 hours. After the reaction was completed, the dichloromethane was removed by evaporation under reduced pressure, and the residue thus obtained was stirred for 30 minutes with 27 ml of hexane and 1.2 g of activated carbon. The activated carbon was removed by filtration, and the filtrate was concentrated to obtain 15 g of 4-[(1-ethoxy)ethoxy]cinnamyl acetoacetate as in the form of an oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(F)c2)CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2ccc(F)c(F)c2)CCNC1
Yield: 63.8 %

Procedure:
Preparation according to Preparation 15. Tert-butyl-3-(3,4-difluorophenyl)-3-methoxypyrrolidin-1-carboxylate (2.65 g, 8.46 mmol), methylene chloride (20 mL) and trifluoroacetic acid (5 mL). Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (1.15 g, 63%). MS m/z (rel. intensity, 70 eV) 198 (46), 183 (79), 171 (bp), 141 (53), 113 (41).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[N:4]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:3]1=[O:21]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccncc3F)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CC(F)(F)F)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
To a solution of N-(3,3-dimethyl-2-oxoindolin-6-yl)-3-fluoroisonicotinamide (example 72, 78 mg, 261 μmol) in DMF (700 μl) under an argon atmosphere was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (66.5 mg, 39.6 μl, 287 μmol) and cesium carbonate (93.4 mg, 287 μmol). After 3 hours at room temperature the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent followed by trituration with diethyl ether/heptane. The title compound was obtained as white foam (36 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][C:10]2([N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][C:11]2([F:25])[F:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][C:10]2([NH:13][CH2:12][C:11]2([F:24])[F:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)N(C(=O)OCc1ccccc1)CC2(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(C1)NCC2(F)F
Reaction time: 14 h
Yield: 81.9 %

Procedure:
To a solution of an optically-active compound of 3,3-difluoro-1,6-diazaspiro[3,4]octane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester (397 mg) in methanol/tetrahydrofuran (3.2 ml/3.2 ml) was added 10% palladium carbon (79 mg), and the mixture was hydrogenated at room temperature under ordinary pressure for 14 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=4/1 to 2/1). The fractions which could not be separated and isolated were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=2/1 to 1/1) again. The purified fractions were combined and concentrated under reduced pressure to give the titled compound (211 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]([CH2:17][CH:18]=[CH2:19])[CH2:14][CH:15]=[CH2:16].[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]=[CH:15][CH2:14][CH:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCC(CC=C)OCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCC(CC=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reaction time: 11 h
Yield: 76.8 %

Procedure:
15 g of the compound (4), 8.3 g of methyl 4-hydroxybenzoate and 23 g of potassium carbonate were dissolved in 100 ml of 2-butanone, and reflux was carried out for 11 hours in an atmosphere of argon. After the solid matter generated was filtered off, the solvent was evaporated, and the residue was purified by a chromatography using a column filled with alumina and silica gel, to obtain 14 g of the compound (5). (Yield: 77%)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([SH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].O>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[C:10]([S:12][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(S)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CSc1cc(C)nc2ccccc12
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
2-methylquinoline-4-thiol 5a (1.00 g, 5.71 mmol, 1.00 eq.) was dissolved in dimethylformamide (10 mL) at room temperature. Potassium carbonate (0.87 g, 6.28 mmol, 1.10 eq.) was added and the mixture was stirred for 15 minutes. Methyl bromoacetate (921 mg, 6.02 mmol, 1.05 eq.) was added dropwise to the solution, and the reaction was stirred at room temperature for 2.5 hours. Water (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (30 mL). The aqueous layer was further extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was dried on high vacuum to yield 5b as a brown solid (1.25 g, 88%).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH3:18][C:19]1[N:20]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22][C:23]=1[C:24](O)=[O:25].C(=O)([O-])O.[Na+]>O>[CH3:18][C:19]1[N:20]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:22][C:23]=1[C:24]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:15])[F:16])=[O:25]
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1sc(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To 25 ml of N,N-dimethylformamide were dissolved 2.60 g (13 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 2.19 g (10 mmol) of 4-methyl-2-phenylthiazole-5-carboxylic acid, followed by the addition of 1.68 g (20 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate ether: hexane=1:9) to obtain 3.03 g (yield: 94%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-phenylthiazole-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:20])[N:6]2[CH2:16][CH2:17][CH2:18][NH2:19].[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>CN1C(=O)CCC1>[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:19][CH2:18][CH2:17][CH2:16][N:6]2[C:5](=[O:20])[NH:4][C:3]3[C:7]2=[N:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][C:2]=3[NH2:1])[CH:26]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN)c2n1
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3cccc(CC(=O)OC)c3)c2n1
Reaction time: 0.25 h

Procedure:
The product from step (ii) (3.1 g) and methyl(3-formylphenyl)acetate (1.6 g) were dissolved in NMP (30 ml) and stirred for 15 min. Sodium triacetoxyborohydride (3.7 g) was added and the mixture stirred at rt for 20 h. After addition of methanol (1 ml), the mixture was purified by SCX, which afforded the subtitle compound. Yield 3.1 g.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH:21](C1C=C2C(=CC=1)C(NC(=O)C1C=CC=CC=1)=NC=C2)=[O:22]>>[CH:21]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1)=[O:22]
Reactant: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Reactant: O=C(Nc1nccc2ccc(Br)cc12)c1ccccc1
Product: O=Cc1ccc2ccnc(NC(=O)c3ccccc3)c2c1

Procedure:
N-(7-Formylisoquinolinyl)benzamide was prepared from 37e using the procedure described for 1f but was not purified using column chromatography. The crude aldehyde was transformed into the title compound using the procedure described for 1g folowed by purification using column chromatography on silica gel (toluene/ethyl acetate: 2/1). M.p. 137.5-139.0° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][NH:19][CH2:20][CH3:21]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:19]([CH3:18])[CH2:20][CH3:21])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CCNC
Solvent: CCO
Product: CCN(C)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), N-methylethanamine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 0.2), 95 (5), 75 (5), 73 (5), 72 (bp), 58 (3).