Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[CH:7]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.[N-:41]=[N+:42]=[N-:43].[Na+]>ClC(Cl)(Cl)Cl.C(O)(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[C:3]([C:2]([F:15])([F:14])[F:1])=[N:43][N:42]=[N:41]2)=[CH:7][C:8]=1[CH3:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(NC(=O)C(F)(F)F)ccc1F
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc(-n2nnnc2C(F)(F)F)ccc1F
Temperature: 100 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
A mixture of 2,2,2-trifluoro-N-(4-fluoro-3-methylphenyl)acetamide (14.3 g) and triphenylphosphine (19.5 g) in tetrachloromethane (140 ml) was stirred for 17 hours at 100° C. An additional triphenylphosphine (5 g) was added to the mixture and the whole was stirred for 5 hours and finally triphenylphosphine (5 g) was added to the mixture, and the whole was stirred further for 15 hours at 100° C. After being cooled to room temperature hexane was added to the reaction mixture and the whole was stirred for 0.5 hour under ice-cooling. The resulting precipitate was removed by filtration and washed with hexane. The combined filtrate and washing were evaporated under reduced pressure below 20° C. A mixture of the syrup obtained and sodium azide (10.6 g) in acetic acid (100 ml) was stirred at room temperature for 7 hours, followed by at 70° C. for 17 hours. After being cooled to room temperature, the mixture was poured into ice-water, and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (100:1-5:1). The fractions containing the objective compound were collected to give 1-(4-fluoro-3-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole (15.2 g) as a syrup.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](Cl)(=O)C(Cl)=O.Cl.CNOC.C[Mg]I>ClCCl.C(N(CC)CC)C.CN(C=O)C>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:10]
Reactant: O=C(O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CNOC
Agent: C[Mg]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1

Procedure:
Scheme 9 depicts synthesis of 2-amino-4-aryl thiazoles of the formula (37) (wherein R4, R5, R6, R7, R8 and R9 are as defined above in description) which is prepared from acetophenones of the formula (36) using known approaches. Certain di- and tri-substituted acetophenones were not commercially available and they were prepared from the corresponding benzoic acid derivative of formula (32) in three steps. Thus, acid of formula (32) was converted to the corresponding acid chloride of formula (33) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane. The acid chloride of formula (33) was converted to corresponding Weinerb amide of formula (35) by treating with N,O-dimethylhydroxylamine hydrochloride of formula (34) in the presence of a suitable base such as triethylamine. The addition of methyl magnesium iodide to Weinreb amide of formula (35) afforded acetophenone derivative of formula (36).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:4]([Cl:9])[CH:3]=1
Reactant: CC(C)=CCBr
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCOc1ccc(Br)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-bromo-2-chlorophenol (1.00 g, 4.82 mmol) and cesium carbonate (3.14 g, 9.64 mmol) in DMF (6.89 mL) at room temperature was added 4-bromo-2-methyl-2-butene (0.68 mL, 5.78 mmol) dropwise via a syringe. The reaction mixture was stirred at 85° C. for 1 hour before it was allowed to cool to room temperature. Water (30.0 mL) was then added and the mixture was extracted with hexane (75.0 mL, 2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the product as a colorless oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:21]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7]>C1COCC1.CO>[F:3][C:4]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[CH:17]=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F)S(=O)(=O)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A 1M solution of NaOH (809 μL, 0.809 mmol) was added to a solution of 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (135 mg, 0.270 mmol) in 4:1 THF/MeOH (1.4 mL, 0.2M). The reaction mixture was stirred at room temperature for 30 minutes. The majority of the organic solvents were removed in vacuo. The resulting residue was acidified with 1N HCl (0.8 mL) and then partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was washed with water (3×10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with minimal CH2Cl2, and the precipitate was filtered and rinsed with Et2O to afford 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide as a solid (48 mg, 45% yield for 2 steps).
Reaction SMILES: [C:1]([C:4]1([NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[N:20]4[C@@:21]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=5)([CH3:33])[C:22](=[O:32])[N:23]([C:24]5[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=5)[C:19]4=[N:18][CH:17]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].[CH2:43](OC(OCC)CBr)[CH3:44].Cl.O1CCOCC1>CC(C)=O>[S:3]1[CH:44]=[CH:43][N:2]=[C:1]1[C:4]1([NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[N:20]4[C@@:21]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=5)([CH3:33])[C:22](=[O:32])[N:23]([C:24]5[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=5)[C:19]4=[N:18][CH:17]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(C(N)=S)CC4)CC3)n21
Reactant: CCOC(CBr)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5nccs5)CC4)CC3)n21
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a solution of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [1-(1-thiocarbamoyl-cyclo-propylcarbamoyl)-cyclopropyl]-amide (92 mg, 0.15 mmol) in 1.5 mL of acetone was added bromoacetaldehyde diethyl acetal (0.089 mL, 0.59 mmol) and HCl in dioxane (4 M, 0.002 mL, 0.01 mmol). The reaction mixture was heated at reflux for 15 h, and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 25 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The organic phase was washed with water and brine (10 mL each), dried over Na2SO4, filtered, and concentrated in vacuo to yield a pale brown oil. The crude product was purified by flash chromatography on silica gel (1-5% MeOH in CH2Cl2), to furnish 30 mg (31%) of the title compound as a pale brown foam, m/z 646.7 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1(N(C)CC)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O>[CH:20]1([CH2:4][N:3]([CH2:2][CH3:11])[C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCN(C)C1CCCC1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1nc2ccccc2cc1C=O
Temperature: 30 °C
Yield: 179.6 %

Procedure:
2-Chloroquinoline-3-carbaldehyde (0.27 grams, 1.40 mmol) and potassium carbonate (0.579 grams, 1.4 mmol) were added to a 25 mL two-necked round bottomed flask. To this flask was added 3 mL of N,N-dimethylformamide (DMF), followed by the drop-wise addition of a dimethylformamide solution of cyclopentyl methyl ethyl amine (0.214 grams, 1.69 mmol). The resulting mixture was refluxed for 2 hours and then cooled to 25-35° C., after which the mixture was poured onto crushed ice (10 mL), and extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to provide the product as yellow oil (0.355 g, yield: 89%).
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44][NH2:45]>C1COCC1.C(OCC)(=O)C>[CH2:18]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:10]([NH:45][CH2:44][C:43]1[CH:46]=[CH:47][C:48]([F:49])=[C:41]([F:40])[CH:42]=1)=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Reactant: NCc1ccc(F)c(F)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)c(F)c1)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a solution of 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (280 mg, 0.835 mmol) and triethylamine (338 mg, 3.34 mmol) in THF (5 mL) at −5° C., isobutyl chloroformate (119.8 mg, 0.876 mmol) was added dropwise. After 20 minutes, 3,4-difluorobenzylamine (131.3 mg, 0.919 mmol) was added and the reaction mixture allowed to warm up to 0° C. for another hour. The mixture was then diluted with ethyl acetate and washed with water, 0.5 N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated with silica gel and purified by column chromatography, eluting with 10˜20% ethyl acetate in hexanes, to give 2-dibenzylamino-N-(3,4-difluoro-benzyl)-3-difluoromethoxy-propionamide (298 mg, 77.5%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.56 (t, 1H), 6.82-7.38 (m, 13H), 6.60 (wt, 1H), 4.58 (dd, 1H), 4.37 (m, 3H), 3.90 (d, 2H), 3.73 (d, 2H) and 3.70 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]([NH:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])([CH3:17])[C:9]([F:16])([F:15])C(OCC)=O)[CH:7]=1.[CH3:26][Mg]Br.[O:29]1[CH2:33][CH2:32]CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@@:8]([NH:18][S@@:19]([C:21]([CH3:24])([CH3:22])[CH3:23])=[O:20])([C:9]([F:16])([F:15])[C:33]([OH:29])([CH3:32])[CH3:26])[CH3:17])[CH:7]=1
Reactant: C[Mg]Br
Reactant: C1CCOC1
Reactant: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Product: CC(C)(C)[S@@](=O)N[C@](C)(c1cc(Br)ccc1F)C(F)(F)C(C)(C)O
Temperature: 23 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of (R)-ethyl 3-(5-bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)-2,2-difluorobutanoate (intermediate A3.2) (10.5 g, 23.6 mmol) in anhydrous tetrahydrofuran (150 ml) at −78° C. was added dropwise a solution of methylmagnesium bromide (3.2 M in 2-methyl-tetrahydrofuran; 59.1 ml, 189 mmol). The cooling bath was removed, and the mixture was stirred at 23° C. for 18 h. Poured cautiously into a saturated solution of ammonium chloride, extracted with ethyl acetate, washed organic layer with brine and dried over sodium sulphate. Removal of the solvent in vacuum left the (R)—N—((R)-2-(5-bromo-2-fluorophenyl)-3,3-difluoro-4-hydroxy-4-methylpentan-2-yl)-2-methylpropane-2-sulfinamide (10.565 g, 23.6 mmol, 99.7% yield) as a yellow gum, which was used in the next step without further purification. MS: m/z=430.1 [(M+H)+] and 432.1 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:33][NH:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([N:34]([CH3:33])[CH2:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: CNCCCN1CCN(C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN1CCN(CCCN(C)C(=O)Cn2c(-c3cccc(Cl)c3)nc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.38 g, 0.008 mole) and 1,1'-carbonyldiimidazole (1.34 g, 0.008 mole) was stirred at room temperature for 3 hours. The N,4-dimethyl-1-piperazinepropanamine (1.42 g, 0.008 mole) was added and the reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was evaporated to dryness. The residue was partitioned between methylene chloride and aqueous potassium bicarbonate. The aqueous layer was separated and extracted with methylene chloride. The methylene chloride layers were combined, extracted with aqueous potassium bicarbonate and water and dried over sodium sulfate. The filtrate was evaporated and the solid residue was recrystallized as a fumarate salt from ethyl alcohol-isopropyl ether. Recrystallization from isopropyl alcohol-acetonitrile-isopropyl ether did not improve the analysis. The solid was converted to the free base. The free base was treated with boiling hexanes and allowed to cool to room temperature. The solid was collected by filtration, washed with hexane, and dried under high vacuum overnight to give 0.7 g of title compound, mp 114°-17° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7](O)[CH:8]=[CH:9][CH2:10][OH:11].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]([CH:3]1[O:11][CH2:10][CH:9]=[CH:8][CH2:7][O:4]1)([CH3:6])([CH3:5])[CH3:1]
Reactant: CC(C)(C)C=O
Reactant: OCC=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)C1OCC=CCO1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A mixture of 430 g (5 moles) of 2,2-dimethylpropanal, 3 g of p-toluenesulfonic acid and 440 g (5 moles) of but-2-ene-1,4-diol in 1000 ml of toluene was refluxed, and the water of reaction formed was removed in the course of 3 hours (h). The mixture was then left to cool to room temperature, 10 ml of a 25% strength sodium hydroxide solution were added to the solution, the mixture was washed neutral with a little water and the toluene was distilled off under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 702 g of 2-tert-butyl-4,7-dihydro-1,3-dioxepin of boiling point 80° C./32 mbar.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(N)ncn2)CC1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.4 g, 3.09 mmol) and diisopropylethylamine (0.399 g, 3.09 mmol) were suspended in n-butanol. tert-Butyl 1,4-diazepane-1-carboxylate 15-1 (0.618 g, 3.09 mmol) was then added. The reaction was stirred at 150° C. for 18 hours and then the product was filtered off, washed with n-butanol and ethyl ether and then air dried. 1H-NMR (CD3OD): 7.95 ppm (s, 1H); 5.65 ppm (s, 1H); 3.73 ppm (m, 2H); 3.61 ppm (m, 3H); 3.55 ppm (t, 1H); 3.38 ppm (m, 1H); 3.34 ppm (m, 1H); 1.89 ppm (m, 1H); 1.84 ppm (m, 1H); 1.41 ppm (s, 4H); 1.36 ppm (s, 5H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([C:17]1([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([OH:31])[CH:25]=2)[CH2:22][CH2:21][O:20][CH:19]([CH3:23])[CH2:18]1)[CH3:16]>>[CH2:15]([C:17]1([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:25]=2)[CH2:22][CH2:21][O:20][CH:19]([CH3:23])[CH2:18]1)[CH3:16]
Reactant: CCC1(c2cc(O)cc(F)c2)CCOC(C)C1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CCC1(c2cc(F)cc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOC(C)C1
Yield: 68 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with (2RS,4SR)-4-ethyl-4-(5-fluoro-3-hydroxyphenyl)-2-methyltetrahydropyran to give (2RS,4SR)-4-ethyl-4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-2-methyltetrahydropyran in 68% yield, as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)=O.[CH3:18][Mg]Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[CH2:18])[CH:16]=1
Reactant: C[Mg]Cl
Reactant: Cc1cccc(C(=O)c2cc(Br)ccc2O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(c1cccc(C)c1)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution (−78° C.) of 99 mg (0.3 mmol) of 5-bromo-2-hydroxy-3′-methylbenzophenone (Compound L) in 5 mL of tetrahydrofuran (under a blanket of argon) was added 1.0 mL (3.0 mmol) of methyl magnesium chloride (3M in tetrahydrofuran). With the addition, the solution turned yellowish-orange in color. The −78° C. bath was removed and the solution was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, extracted between ethyl acetate and sat. NH4Cl (aq.) solution and the layers were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give crude 4-bromo-2-[(1-m-tolyl-1-hydroxy)ethyl]phenol as a yellow oil. The crude alcohol was dissolved in 2 mL of toluene, placed under a blanket of argon and 5.9 mg of p-toluene sulfonic acid monohydrate was added. The resultant mixture was heated at 70° C. for 45 minutes, cooled to ambient temperature and purified by flash chromatography (silica, 5% ethyl acetate in hexane) to give the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)S(O[CH2:34][C:35]([F:43])([F:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=O)=O.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:34][C:35]([F:43])([F:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCC(F)(F)c3ccccc3)c2CC1
Temperature: 40 °C
Yield: 55.9 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (10 mL) and add potassium hydroxide (0.934 g, 16.64 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.163 g). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.163 g, 0.52 mmol) in anhydrous DMSO (5 mL) and add triethylamine (0.43 mL, 3.12 mmol) and 2,2-difluoro-2-phenylethyl trifluoromethanesulfonate (151 mg, 0.52 mmol). Heat the solution at 40° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1, 9:1 and 4:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (132 mg, 56%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=[O:15].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].C(O)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O-:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([O-:16])=[O:15].[NH3+:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH3+:24]
Reactant: O=C(O)c1ccc2ccc(C(=O)O)cc2c1
Reactant: NCCCCCCN
Solvent: O
Solvent: CCO
Product: O=C([O-])c1ccc2ccc(C(=O)[O-])cc2c1
Product: [NH3+]CCCCCC[NH3+]

Procedure:
Equimolar proportions of naphthalene-2,7-dicarboxylic acid and hexamethylene diamine were dissolved in water to form a salt. Then, ethyl alcohol was added to form hexamethylene diammonium naphthalene-2,7-dicarboxylate as a white powder which did not contain water of crystallization.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[S:6][CH:7]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[N:4]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)cs1
Reactant: COC(=O)Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1csc(CCc2nc(-c3ccccc3)oc2C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
To a mixture of 4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole (0.64 g), methyl 2-(2-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate as a colorless oil (0.49 g, 60%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).