Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[OH:27])[N:10]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[F:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:27])[C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:38](=[O:39])[O:40][CH2:41][CH3:42])[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3c(O)cccc3F)nc2c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: 60 °C
Yield: 38.9 %

Procedure:
To a stirred solution of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (200 mg, 0.54 mmol) in 12 mL THF was added diisopropyl ethylamine (188 μL, 1.08 mmol) at room temperature. The mixture was cooled to—60° C., and a solution of ethyl chloroformate (52 μL, 0.54 mmol) in 0.6 mL THF was added dropwise. After allowing the reaction to warm to room temperature, the mixture was partitioned between H2O and CH2Cl2. The layers were separated, and the aqueous layer was extracted twice more with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 hexanes:CH2Cl2 gave ethyl ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (92 mg, 38%). LC/MS: m/z 439.5 (M+H)+ at 2.40 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH3:20].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:17][CH2:18][O:19][CH3:20])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(=O)OC)cc(C(C)(C)C)c1

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 2.18 g) and 1-bromo-2-methoxyethane (1.18 ml) were dissolved in DMF (30 ml) and sodium hydride (301 mg) was added while stirring. After stirring at RT for 2 h, the solvent was drawn off. The residue was taken up in EA, and the mixture was washed with water, dried and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/MtB ether gradient of 0-30% in 60 min). 2.0 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:19])[N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:16]2[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]([CH3:11])[CH:17]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1cc(O)cc(C)n1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(Br)cc2C=O)cc(C)n1

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with 2,6-dimethyl-4-hydroxypyridine (2.5 g, 20 mmol) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(2,6-dimethyl-pyridin-4-yloxy)-benzaldehyde as an off white solid (Yield 6 g, 98%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.[C:18](=O)(O)[O-].[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(O)c(I)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(O)c(I)c1

Procedure:
A solution of 3-iodo-4-hydroxybenzoic acid (28.76 g, 0.11 mol) and sulphuric acid (6.6 ml) in methanol (160 ml) is refluxed for 6 h. 300 ml of water are added and the mixture is basified with sodium bicarbonate until neutral. It is extracted with ethyl ether (600 ml). The organic phase is washed with twice 400 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on the column of silica (10% ethyl acetate, 90% CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.O.O.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:11]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C2(C#N)CC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of methyl 2-chloro-3-(1-cyanocyclopropyl)benzoate (13.5 g, 57.3 mmol) in tetrahydrofuran (180 mL)/methanol (60 mL)/water (60 mL) was added lithium hydroxide monohydrate (3.62 g, 86.3 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and 6N hydrochloric acid (20 mL) was added dropwise to the obtained residue. The precipitate was collected by filtration, and washed with water to give the title compound (11.4 g, 90%) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[O:6][NH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[C:24]4[C:25]([C:29]([O:31]C)=[O:30])=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]3[CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)=[N:3]1.[OH-].[Na+].Cl>>[O:1]=[C:2]1[O:6][NH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[C:24]4[C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[C:21]3[CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)=[N:3]1
Reactant: CCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nc(=O)o[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A mixture of methyl 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-propylbenzimidazole-7-carboxylate (703 mg) in 0.3N-NaOH (12 ml) was stirred at 60° C. for one hour, and then adjusted to pH 3 with 0.1N-HCl. Resulting precipitates were extracted with a mixture of chloroform-ethanol (10:1; 150 ml). The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol to give the title compound as colorless prisms (550 mg, 90%), m.p.169°-171° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[S:7][C:8]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:9]=3[N:10]=2)[CH2:2]1.[C:18](O)(=O)[CH3:19].[C:22](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CC(C)=O>[CH:18]([N:1]1[CH2:5][CH2:4][CH:3]([C:6]2[S:7][C:8]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:9]=3[N:10]=2)[CH2:2]1)([CH3:19])[CH3:22]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)Cc1sc(C3CCNC3)nc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: CC(C)N1CCC(c2nc3c(s2)Cc2ccccc2-3)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 75 mg of 2-(3-pyrrolidinyl)-8H-indeno[1,2-d]thiazole in 1.4 ml of methylene chloride, were added 0.18 ml of acetic acid, 0.045 ml of acetone, and 147 mg of sodium triacetoxyborohydride, followed by stirring at room temperature for 2 hours. Water and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture. The resulting mixture was extracted with chloroform, followed by drying over anhydrous magnesium sulfate. The solvent was then evaporated and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol:29% ammonium=300:10:1), whereby 30 mg of 2-(1-isopropyl-3-pyrrolidinyl)-8H-indeno[1,2-d]thiazole was obtained. The resulting product was dissolved in methanol. Fumaric acid was added to cause crystallization, and crystals were recrystallized from acetonitrile-methanol to give a fumarate.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[ClH:11].[CH3:12][OH:13]>>[ClH:11].[CH3:12][O:13][C:1](=[NH:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C#N)cc1
Reactant: CO
Agent: Cl
Product: COC(=N)c1ccc(OC)cc1
Temperature: 0 °C

Procedure:
25 g of anisonitril was dissolved in 250 ml of methanol. After saturation with hydrogen chloride gas under cooling in ice-water and stirring, the solution was stirred at room temperature for 15 hours. Then, methanol was evaporated in vacuo. Ether was added to the residue and the crystals were filtered off and dried. Whereby 35.9 g of the desired substance was obtained as white crystals. Melting point is 111° to 112° C. (Decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:26]=[C:27]([CH3:29])[CH:28]=2)=[CH:16][CH:15]=1)#[N:13].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:30]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:25]1[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([O:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[CH:24]=1)(=[O:10])=[O:9]
Reactant: CCOC(=O)CNc1cc(C)cc(OCCc2ccc(C#N)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)CN(c1cc(C)cc(OCCc2ccc(C#N)cc2)c1)S(=O)(=O)c1ccccc1Cl
Reaction time: 2 h
Yield: 62 %

Procedure:
2-Chlorobenzenesulfonyl chloride (0.225 g; 1.06 mmol) was added to a cold solution (ice:water temperature) of 3-[2-(4-cyanophenyl)ethoxy]-5-methyl-phenylaminoacetic acid, ethyl ester (0.30 g; 0.88 mmol; from step (i) above) in pyridine (10 mL). After 2 hours stirring the temperature was allowed to rise to ambient. After 4 hours at this temperature more 2-chloro-benzenesulfonyl chloride (0.056 g; 0.26 mmol) was added and the mixture was left overnight. The mixture was then poured into aqueous saturated NaHCO3 and extracted twice with Et2O. The combined ether phases where washed with HCl/aq (2M), H2O and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (SiO2; EtOAc:heptane (1:3)) to give 0.28 g (62%) of the sub-title compound.
Reaction SMILES: C([CH:3]=[CH:4][CH2:5][NH2:6])C.[C:7](=[S:9])=[S:8].[CH3:10][CH2:11]O[CH2:13][CH3:14]>>[CH2:5]([NH:6][CH2:10][CH3:11])[CH:4]=[CH2:3].[CH2:5]([N:6]([CH2:13][CH3:14])[C:7](=[S:8])[SH:9])[CH:4]=[CH2:3]
Reactant: CCOCC
Reactant: S=C=S
Reactant: CCC=CCN
Product: C=CCN(CC)C(=S)S
Product: C=CCNCC
Reaction time: 0.25 h

Procedure:
A quantity of 3.57 grams (g) of ethylallyl amine (0.042 mole) plus 1.52 g of carbon disulfide (0.02 mole) was charged into a beaker containing 50 mililliters (ml) of ether. The reaction mixture was allowed to let stand for approximately 15 minutes and the volatiles were then stripped off, leaving behind a residue of 4.9 g of a yellow solid, which was identified by conventional analytical techniques as being the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[CH:7][C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[OH:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:25][CH3:26])[CH:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2=[O:18]
Reactant: CCOC(=O)c1cnc2cc(Cl)c(Br)cc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(Cl)c(Br)cc2c1=O
Temperature: 80 °C

Procedure:
33 g of the above compound were added to 50 cm3 of Dowtherm, heated at 250° C. and stirred in a round-bottomed flask equipped with a descending condenser which enabled the alcohol formed in the reaction to be collected; the reaction was complete after heating for 15 minutes. After cooling, the contents of the round-bottomed flask were taken up in 200 m3 of ethyl acetate. The solid was separated and recrystallised from dimethylformamide. 27.9 g of 6-bromo-7-chloro-3-ethoxycarbonyl-4-hydroxy-quinoline, m.p. 368°-370° C. (decomposition), were obtained. 13 g of 6-bromo-7-chloro-3-ethoxycarbonyl-4-hydroxyquinoline, 11 g of potassium carbonate and 100 cm3 of dimethylformamide were heated at 110° C. for 1 hour, whilst stirring. After cooling to 80° C., 16 cm3 of ethyl iodide were added to the mixture which was stirred and heated at 110° C. for 4 hours. After concentration to dryness in vacuo, the residue was taken up in 200 cm3 of water. The mixture was extracted with chloroform (3×100 cm3), and the combined organic extracts were washed with water, dried (MgSO4) and concentrated to dryness. The residue, recrystallised from 95 cm3 of isopropanol, gave 10 g of 6-bromo-7-chloro-1-ethyl-4-oxo-1,4-dihydro-3-ethoxycarbonylquinoline, m.p. 166° C. 10 g of the above ester were added to an aqueous-alcoholic solution of sodium hydroxide (NaOH:2.25 g, water:50 cm3, ethanol:100 cm3). The mixture was heated under reflux for 30 minutes. The solution was concentrated to dryness in vacuo. The residue was suspended in 100 cm3 of water. The solution was acidified by adding 3.4 cm3 of acetic acid. The solid was separated and recrystallised from DMF (90 cm3). 8.1 g (89%) of 6-bromo-7-chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 320° C. (decomposition), were obtained.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[N:19]1(NC(OC(C)(C)C)=O)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O1CCC(=O)CC1.N1CCC(N[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])CC1>>[CH2:11]([O:10][C:9]([NH:8][CH:5]1[CH2:6][CH2:7][CH:2]([N:22]2[CH2:23][CH2:24][N:19]([C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])[CH2:20][CH2:21]2)[CH2:3][CH2:4]1)=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: O=C1CCOCC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCC(NC(=O)OCc3ccccc3)CC2)CC1
Yield: 96 %

Procedure:
The title compound 4.0 g (96%) was obtained in a manner similar to the Manufacturing Example 83 by use of benzyl 4-oxocyclohexylcarbamate and tert-butyl 1-piperazinecarbamate, instead of tetrahydro-4H-pyran-4-one and tert-butyl piperidin-4-ylcarbamate, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Temperature: 80 °C
Yield: 83 %

Procedure:
To methyl 3-chloro-4-hydroxy-benzoate (3.0 g, 16.1 mmol) in DMF (19 mL) was added potassium carbonate (8.9 g, 64.3 mmol) followed by 2-iodopropane (5.5 g, 3.2 mL, 32.2 mmol). The reaction mixture was heated at 60° C. for 1.5 hours. The reaction mixture was cooled, filtered and diluted with EtOAc and the solvent was concentrated in vacuo. The material was dissolved in EtOAc and washed with water (3×10 mL) and brine (1×10 mL). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo to give methyl 3-chloro-4-isopropoxybenzoate. To the ester was added dioxane (47 mL) and sodium hydroxide (42.7 mL of 1 M, 42.7 mmol) and the reaction was heated at 80° C. for 15 minutes. The reaction was cooled and solvent was removed in vacuo. The resulting residue was dissolved in water and washed with EtOAc (3×10 mL) and the layers were separated. The aqueous layer was acidified to pH 1 and was extracted with EtOAc (3×10 mL). The organic layer was separated and dried over Na2SO4, filtered and the solvent was removed in vacuo to yield 3-chloro-4-isopropoxy-benzoic acid (2.86 g, 83%) as a white solid. ESI-MS m/z calc. 213.6. Found 215.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400.0 MHz, CDCl3) δ 8.05 (d, J=2.2 Hz, 1H), 7.90-7.87 (dd, J=8.8, 2.2H, 1H), 7.06 (d, J=8.8 Hz, 1H) and 3.90 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[CH3:12][C:13](=[CH:15][CH2:16]Br)[CH3:14]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])[CH:4]=1
Reactant: COc1cccc(S)c1
Reactant: CC(C)=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cccc(SCC=C(C)C)c1
Yield: 90.4 %

Procedure:
50.45 g (360.0 mmol) of 3-methoxythiophenol, 360 ml of acetone and 14.40 g (360.0 mmol) of sodium hydroxide pellets are introduced into a one liter round-bottomed flask under a nitrogen atmosphere and the mixture is heated at reflux for three hours. A solution composed of 53.65 g (360.0 mmol) of 2-methyl-4-bromo-2-butene and of 60 ml of acetone is added dropwise. Reflux is maintained for sixteen hours and the reaction mixture is evaporated to dryness. Water is added, extraction is carried out with ethyl acetate, the organic phase is washed with water and then using a saturated sodium chloride solution, dried over magnesium sulphate and filtered, and the solvents are evaporated. The residue obtained is distilled under reduced pressure (5×10−2 bar/113° C.) to produce 67.81 g (90%) of the expected compound in the form of a pale-yellow oil.
Reaction SMILES: C([O:4][C:5]1[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:8]([C:9]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:19][C:18]([CH3:29])=[CH:17][C:16]=3[CH3:30])=[O:10])=[CH:7][C:6]=1[CH:36]([CH3:38])[CH3:37])(=O)C.[OH-].[Na+]>CO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:20]2[C:15](=[C:16]([CH3:30])[CH:17]=[C:18]([CH3:29])[CH:19]=2)[N:14]=[CH:13][C:12]=1[NH:11][C:9](=[O:10])[C:8]1[CH:7]=[C:6]([CH:36]([CH3:38])[CH3:37])[C:5]([OH:4])=[C:32]([CH:33]([CH3:35])[CH3:34])[CH:31]=1
Reactant: CC(=O)Oc1c(C(C)C)cc(C(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c2ncc(NC(=O)c3cc(C(C)C)c(O)c(C(C)C)c3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A mixture of 3-(4-acetoxy-3,5-diisopropylbenzamido)-4-(2-chlorophenyl)-6,8-dimethylquinoline (600 mg), methanol (40 ml) and 1N-sodium hydroxide (4 ml) was stirred at room temperature for 3 hours. After concentrating, the mixture was diluted with water and made acidic with 2N-hydrochloric acid. Thereafter, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed and the residue was recrystallized from acetone-isopropyl ether to give 4-(2-chlorophenyl)-3-(4-hydroxy-3,5-diisopropyl benzamido)-6,8-dimethylquinoline (494 mg, 89.5%) as colorless prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH:5]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[CH:6]([OH:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[C:23]([O-])(=[O:25])[CH3:24].[Na+].O>C(OC(=O)C)(=O)C>[ClH:1].[C:23]([O:12][CH:6]([C:7]([CH3:11])([CH3:10])[CH2:8][F:9])[CH:5]([O:4][C:3]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=1[Cl:1])[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: CC(C)(CF)C(O)C(Oc1ccc(Cl)cc1Cl)n1ccnc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1Cl)n1ccnc1)C(C)(C)CF
Product: Cl
Temperature: 100 °C
Reaction time: 10 h
Yield: 2948.3 %

Procedure:
17.3 g (0.05 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(imidazol-1-yl)-butan-2-ol were dissolved in 100 ml of acetic anhydride and, after adding 0.1 g of sodium acetate, the mixture was stirred at 100° C. for 10 hours. Thereafter, the reaction solution was allowed to cooled to room temperature, stirred into 500 ml of water and left to stand for 15 hours. The aqueous phase was extracted twice with 200 ml of methylene chloride each time. The combined organic phases were washed with 100 ml each of sodium bicarbonate solution and water, dried over sodium sulphate and concentrated in vacuo. The residue was taken up in 100 ml of ether, 20 ml of ethereal hydrochloric acid were added, the solvent was distilled off in vacuo and the residue was stirred with 50 ml of ether. 15.3 g (72% of theory) of 2-acetoxy-1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(imidazol-1-yl)-butane hydrochloride of melting point of 198°-200° C. were obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[CH:15]1([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[S:29])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[BrH:1].[CH:15]1([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]3[S:29][CH:2]=[C:3]([C:5]4[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=4[CH3:10])[N:30]=3)=[CH:25][CH:26]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: NC(=S)Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccc(C4CCCCC4)cc3)n2)c(C)s1
Yield: 42.1 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (65 mg, 0.21 mmol) was allowed to react with 4-cyclohexylphenylthiourea (49.2 mg) as described in Example 154, step (a) to give 45 mg (41% yield) of methyl 4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ1.23-1.39 (m, 5H), 1.71-1.79 (m, 5H), 2.68 (s, 3H), 3.83 (s, 3H), 7.16 (d, 2H, J=8.6 Hz), 7.26 (s, 1H), 7.65 (d, 2H, J=8.7 Hz), 8.14 (s, 1H), 10.19 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C22H24N2O2S3, 444.64 (M+H), found 445.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][OH:20])=[O:17])=[N:14][CH:15]=1.[Si:32]([O:49][CH2:50][CH2:51]O)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Si:32]([O:49][CH2:50][CH2:51][O:20][CH2:19][NH:18][C:16]([C:13]1[CH:12]=[C:11]([CH3:21])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:15][N:14]=1)=[O:17])([C:45]([CH3:46])([CH3:47])[CH3:48])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C(=O)NCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1cc(C(=O)NCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 60 °C
Yield: 50.6 %

Procedure:
5-[(2,5-Difluorophenyl)[(4-fluorophenyl)sulfonyl]meth yl]-N-(1-hydroxymethyl)-4-methylpyridine-2-carboxamide (113 mg, 0.251 mmol) obtained in Example 85, and a solution of 2-(tert-butyldiphenylsilyloxy)ethanol (136 mg, 0.453 mmol) and p-toluenesulfonic acid (10 mg) in benzene (5 ml) were stirred for 3 hours with heating to 60° C. The reaction solution was returned to room temperature, and then was concentrated under reduced pressure. Ethyl acetate was added to the resulting concentration residue, and the mixture was washed sequentially with saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with 25% ethyl acetate/hexane was concentrated under reduced pressure, to obtain the title compound (93 mg, 0.127 mmol, 51%) as an amorphous substance.