Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N([CH2:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:10]([Cl:24])[CH:9]=2)N=NC=1C(N)=O.C(Cl)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>CN(C)C=O.ClC1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([C:11]2[C:12]([Cl:14])=[CH:13][C:8]([CH3:7])=[CH:9][C:10]=2[Cl:24])=[O:23])=[CH:17][CH:18]=1
Reactant: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1

Procedure:
Compound 1 can be prepared by the method described in U.S. Pat. No. 4,590 201 Briefly, 2 6-dichloro-4-methylbenzoic acid is converted to its corresponding benzoyl chloride using thionyl chloride in dimethylformamide. Reaction of this benzoyl chloride with chlorbenzene in the presence of aluminum trichloride provides 4-(4-chlorobenzoyl)-3,5-dichlorotoluene. Bromination of the methyl group is carried out using N-bromosuccinimide in the presence of catalytic amounts of dibenzoyl peroxide to provide 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide. The benzyl bromide is then converted to the corresponding benzyl azide using potassium azide. Treatment of the 4(4-chlorobenzoyl)-3,5-dichlorobenzyl azide thus formed with 2-cyanoacetamide in the presence of sodium methoxide provides after workup, 5-amino-l-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)- 1,2,3-triazole-4-carboxamide (Compound 1).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=1[F:15])([CH3:4])([CH3:3])[CH3:2].N>CO.[Ni]>[NH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])=[C:8]([F:15])[CH:9]=1
Reactant: CC(C)(C)NC(=O)c1ccc(C#N)cc1F
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)NC(=O)c1ccc(CN)cc1F
Yield: 150.3 %

Procedure:
Combine N-tert-butyl-4-cyano-2-fluoro-benzamide (0.6 g, 1.78 mmol), Raney® 3201 nickel (slurry in water, 30 mg), 2N ammonia in methanol (30 mL) and hydrogenate at 50 psi for 1 h. Filter the reaction mixture through a pad of Celite®, concentrate in vacuo and purify by SCX chromatography to obtain the title compound as a colorless oil (0.6 g, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([OH:17])=O)[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:54][NH:55][O:56][CH3:57].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([N:55]([CH3:54])[O:56][CH3:57])=[O:17])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:5])[CH3:2]
Reactant: CNOC
Reactant: CCOC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H](CC1CCCCC1)C(=O)N(C)OC
Reaction time: 0.05 h

Procedure:
To 0.5 mL CH2Cl2 was added 48.6 mg (200 μmole) of EtOCO-Cha, 34.8 μL (200 μmole) DIEA, and 88.4 mg (200 μmole) BOP. After 3 min, 19.4 mg (200 μmole) N,O-dimethyl-hydroxylamine.HCl and 34.8 μL (200 μmole) DIEA were added. The reaction was monitored by TLC, and after 90 min it was diluted with CH2Cl2, washed 2× with dilute HCl and 2× with saturated NaHCO3. The organic layer was dried with Na2SO4, filtered, and the filtrate evaporated by rotary evaporation to give the title compound. NMR (300 MHz, CDCl3): a 4.72 (br m, Cha-α, 1H), 4.04 (q, CH3CH2OCO, 2H), 3.72 (s, N(CH3)OCH3, 3H), 3.13 (s, N(CH3)OCH3, 3H), 1.17 (t, CH3CH2OCO, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([F:14])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([F:15])[CH:4]=1.[Cl:16][C:17]1[CH:18]=[C:19]([OH:27])[CH:20]=[N:21][C:22]=1[O:23][CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([O:27][CH2:2][C:3]2[C:13]([F:14])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([F:15])[CH:4]=2)[CH:20]=[N:21][C:22]=1[O:23][CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)Oc1ncc(O)cc1Cl
Reactant: CCOC(=O)c1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)c(COc2cnc(OC(C)C)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 144 %

Procedure:
To a solution of ethyl 4-(bromomethyl)-2,5-difluorobenzoate (Preparation 13, 200 mg, 0.72 mmol) in N,N-dimethylformamide (4 mL) at room temperature under nitrogen was added 5-chloro-6-isopropoxypyridin-3-ol (Preparation 6, 161 mg, 0.86 mmol) and potassium carbonate (198 mg, 1.43 mmol). The reaction was stirred at room temperature for 2 days, then partitioned between water and ethyl acetate (1:1 10 mL). The organic phase was washed with brine (10 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a light yellow solid (400 mg, >100%). No further purification undertaken.
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=1>C(NC(C)C)(C)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:4]#[C:5][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1ccc(Br)cn1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#CC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Cyclopropylacetylene (73.7 μL), copper iodide (3.16 mg) and tetrakis(triphenylphosphine)palladium (9.59 mg) were added to a solution of ethyl 5-bromopyridine-2-carboxylate (95.5 mg) in diisopropylamine (2 mL) at room temperature, and the mixture was stirred at room temperature for 17 hours and five minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (19.4 mg).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)(O)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC1CCC(O)(c2cccc(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCC1=CCC(c2cccc(F)c2)CC1
Temperature: 30 °C
Yield: 93.6 %

Procedure:
The compound (10) (80.0 g), p-toluenesulfonic acid (2.4 g) and toluene (250 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture obtained was cooled to 30° C., and then water (500 ml) and toluene (900 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation into an organic phase was carried out. The organic phase obtained was fractionated, washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and dried, giving 70.3 g of 4-heptyl-1-(3-fluorophenyl)-3-cyclohexene (11). The yield based on the compound (11) was 94.0%.
Reaction SMILES: [Na:1].[C:2]([OH:7])(=[O:6])[C:3]([CH3:5])=[CH2:4].[CH2:8]1[O:10][CH2:9]1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[CH:11]([CH2:4][C:3](=[CH2:5])[C:2]([OH:7])=[O:6])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na:1].[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].[CH2:9]1[O:10][CH2:8]1
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: C1CO1
Solvent: O
Product: C=C(CC=Cc1ccccc1)C(=O)O
Reaction time: 5 h

Procedure:
683 parts of water, 11 parts of a sodium salt of a sulfate ester of an adduct of ethylene oxide methacrylate (ELEMINOL RS-30: manufactured by Sanyo Chemical Industries, Ltd.), 138 parts of styrene, 138 parts of methacrylic acid, and 1 part of ammonium persulfate were stirred for 15 minutes at 400 r.p.m. in a reaction vessel equipped with a stirring rod and a thermometer to obtain a white emulsion. The emulsion was heated until the temperature in the system reached 75° C., and allowed to react for five hours. The reactant was further added with 30 parts of 1% ammonium persulfate aqueous solution, and aged at 75° C. for five hours to obtain an aqueous dispersion of a vinyl resin (copolymer of styrene-methacrylic acid-sodium salt of sulfate ester of an adduct of ethylene oxide methacrylate) [fine particle dispersion 1]. The volume average particle diameter of [fine particle dispersion 1]measured by a LA-920 was 0.14 μm. A part of [fine particle dispersion 1]was dried to isolate the resin component. The Tg of the resin component was 152° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12](Cl)=[O:13]>[Cl-].[Zn+2].[Cl-].Cl>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[C:12]([C:11]1[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=1[F:19])=[O:13]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Nc1ccc(Br)cc1C(=O)c1c(F)cccc1F
Temperature: 180 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
4-Bromoaniline (14.9 g, 86.5 mmol) was heated to 120° C. and 2,6-difluorobenzoyl chloride (36.7 g, 208 mmol) was added. The temperature of the mixture was raised to 180° C. and zinc chloride (14.2 g, 104 mmol) was added. The temperature of the mixture was raised to 205° C. and the mixture was stirred for 3 hrs. The reaction mixture was cooled to 150° C., and 4N hydrochloric acid (100 ml) was added, and the mixture was heated under reflux for 15 min. The supernatant was removed, 4N hydrochloric acid (100 ml) was added to the residue, and the mixture was heated under reflux for 15 min. The supernatant was removed and the residue was dissolved in acetic acid (85 ml). Conc. hydrochloric acid (85 ml) was added at 120° C. and the mixture was heated under reflux for 12 hrs. The reaction mixture was concentrated under reduced pressure and 1N aqueous sodium hydroxide solution (200 ml) was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give a crude product of (2-amino-5-bromophenyl)(2,6-difluorophenyl)methanone (7.8 g). To a solution of the crude product (5.2 g) and 5-methyl-3-oxohexanenitrile (2.1 g, 17 mmol) in toluene (100 ml) was added methanesulfonic acid (1.6 g, 17 mmol) and the mixture was heated under reflux for 17 hrs. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 6-bromo-4-(2,6-difluorophenyl)-2-isobutylquinoline-3-carbonitrile (1.6 g, yield 4.6%) as a yellow solid.
Reaction SMILES: COC(=O)CC1CC2C(=CC(OCC(N=C=O)OC(C)(C)C)=CC=2)NC1=O.[CH3:28][O:29][C:30](=[O:57])[CH2:31][C:32]1[C:33](=[O:56])[N:34]([CH2:54][CH3:55])[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][CH2:45][NH:46]C(OC(C)(C)C)=O)[CH:36]=2>>[CH3:28][O:29][C:30](=[O:57])[CH2:31][C:32]1[C:33](=[O:56])[N:34]([CH2:54][CH3:55])[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][CH2:45][NH2:46])[CH:36]=2
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCNC(=O)OC(C)(C)C)cc21
Agent: COC(=O)CC1Cc2ccc(OCC(N=C=O)OC(C)(C)C)cc2NC1=O
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCN)cc21

Procedure:
The title compound is prepared according to the procedure of Example 78 except that [7-(2-tert-butoxy-carbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]acetic acid methyl ester is replaced with [7-(3-tert-butoxycarbonylaminopropoxy)-1-ethyl-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[C:27]([CH3:28])=[CH:26][N:25]([CH3:29])[C:24](=[O:30])[C:14]=4[C:15]([O:16]CC4C=CC=CC=4)=[C:9]3[C:8]2=[O:31])=[CH:4][CH:3]=1>[OH-].[OH-].[Pd+2].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[C:27]([CH3:28])=[CH:26][N:25]([CH3:29])[C:24](=[O:30])[C:14]=4[C:15]([OH:16])=[C:9]3[C:8]2=[O:31])=[CH:32][CH:33]=1
Reactant: Cc1cn(C)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(Cc1ccc(F)cc1)C3=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn(C)c(=O)c2c(O)c3n(c12)CCN(Cc1ccc(F)cc1)C3=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8-(4-fluorobenzyl)-10-benzyloxy-2,4-dimethyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (27 mg, 0.06 mmol) and Pearlman's catalyst (2.5 mg, 20% Pd(OH)2 on carbon) in ethanol (5 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 1 hr. The reaction product precipitated out of solution. The suspension was treated with chloroform, and the mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue recrystallized from ethanol to provide the title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](F)=[CH:9][C:8]([F:12])=[CH:7][N:6]=1)=[O:4].FC1C=CC(C(O)=O)=NC=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:12])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(F)cc1F
Agent: O=C(O)c1ccc(F)cn1
Product: COC(=O)c1ccc(F)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 175a, from 5-fluoropicolinic acid (1.05 g, 7.44 mmol) to give a yellow solid (980 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=2.78 Hz, 1 H) 8.21 (dd, J=8.72, 4.42 Hz, 1 H) 7.55 (d, J=3.03 Hz, 1 H) 4.02 (s, 3 H); LCMS for C7H6FNO2 m/z 156.00 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.CC(C)([O-])C.[K+:43]>C(O)C.C(O)(C)(C)C>[K+:43].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O-:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)(C)O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)[O-])ccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A stirred suspension of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (179 g, 0.335 mol) in ethanol (2.6 L) was treated with 1 N potassium tert-butoxide in tert-butyl alcohol (350 mL) and stirred at room temperature under N2 for 1 hour. The mixture was then heated to a gentle reflux for 2 hours and was stirred overnight at room temperature. The suspension was filtered, then the filter cake was washed with hexane, combined with 5 g of similarly prepared material and dried at 60° C. in a vacuum oven overnight to yield 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid potassium salt as a beige solid (181 g, 84%). 1H NMR (400 MHz, DMSO-d6): 8.25 (d, J=9 Hz, 1H), 8.18 (d, J=9 Hz, 1H), 8.08 (d, J=2 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.94 (dd, J=2, 9 Hz, 1H), 7.68 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.53 (dd, J=7, 9 Hz, 1H), 6.90 (d, J=9 Hz, 2H), 4.86 (s, 2H), 3.46 (m, 1H), 1.32 (d, J=7 Hz, 6H). ES-LCMS m/z 533 (M+H)+.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH:9]=1)[OH:8].CN(C)C=O.Cl[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20]>O>[CH3:20][O:19][CH:18]([O:21][CH3:22])[CH2:17][O:8][C:7]1[CH:9]=[C:3]([CH3:2])[CH:4]=[C:5]([OH:10])[CH:6]=1
Reactant: COC(CCl)OC
Reactant: Cc1cc(O)cc(O)c1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1cc(C)cc(O)c1)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The monosodium salt of 5-methylresorcinol prepared in Example 4 and dimethyl formamide (200 ml) were charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. 1-Chloro-2,2-dimethoxyethane (6.25 grams) was added, and the mixture was heated at 85° to 90° C. and stirred for a period of about 221/2 hours. After this time the reaction mixture was cooled to room temperature and was added to 1200 ml of water. The resulting mixture was carefully neutralized and extracted with chloroform. The organic phase was then separated from the aqueous phase and stripped of solvent, leaving a liquid residue. The residue was distilled under reduced pressure to yield a yellow viscous liquid which solidified upon cooling to -10° C. This product was then recrystallized from a methanol-water mixture, was washed with boiling water and dried to yield the desired product 3-(2,2-dimethoxyethoxy)-5-hydroxytoluene as a white solid melting at 73° to 75° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:12](=[O:22])[CH:11]=2)=[N:6][CH:7]=1.OC1C=NN(C2CCCCO2)C(=O)C=1.[F:37]C1C=CC(CO)=NC=1>>[F:37][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:12](=[O:22])[CH:11]=2)=[N:6][CH:7]=1
Reactant: OCc1ccc(F)cn1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cnn1C1CCCCO1
Agent: O=c1cc(O)cnn1C1CCCCO1
Product: O=c1cc(OCc2ccc(F)cn2)cnn1C1CCCCO1

Procedure:
5-(5-Fluoro-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one is prepared following preparation 18a from 2.40 g (12.2 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (see preparation 5a) and 1.56 g (12.2 mmol) (5-fluoro-pyridin-2-yl)-methanol
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:20]1[CH:36]=[CH:35][C:23]2[N:24]=[C:25]([CH2:27][S:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[NH:26][C:22]=2[CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:12]([C:20]1[CH:36]=[CH:35][C:23]2[N:24]=[C:25]([CH2:27][S:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[O:6])[NH:26][C:22]=2[CH:21]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(CSc3ccccn3)[nH]c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc2nc(CS(=O)c3ccccn3)[nH]c2c1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
10.1 g (0.05 mole) of 85% pure m-chloroperoxybenzoic acid are added slowly to a solution, cooled to -15° C., of 17.3 g (0.05 mole) of 5-benzoyl-2-(2-pyridylthiomethyl)benzimidazole in 250 ml of dichloromethane. The mixture is stirred at a temperature below -10° C. for 30 minutes and 100 ml of sodium carbonate solution are added. The organic phase is decanted, washed with sodium carbonate and water and then dried (Na2SO4). When this has been filtered, the solvent is evaporated off and the residue recrystallized in acetone. 12.0 g (66.5%) of 5-benzoyl-2-(2-pyridylsulfinylmethyl)benzimidazole, melting point 142°-145° C., are obtained.
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:41]([C:40]([F:39])([F:55])[F:54])[CH:42]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as an orange oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3,5-bis(trifluoromethyl)phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[C:5]([O:14][CH2:15][CH3:16])=[C:6]([C:8]2([CH3:13])OCC[O:9]2)[CH:7]=1.Cl.O>CO>[C:8]([C:6]1[C:5]([O:14][CH2:15][CH3:16])=[C:4]([CH:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[C:3]([F:23])=[C:2]([Cl:1])[CH:7]=1)(=[O:9])[CH3:13]
Reactant: CCOc1c(C2(C)OCCO2)cc(Cl)c(F)c1C1CNC(=O)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1CNC(=O)C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
The separated enantiomers from step 4 were each processed individually to the final compounds. A solution of 4-[3-chloro-6-ethoxy-2-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]pyrrolidin-2-one (1.7 g, 5.0 mmol) (from Step 4) in methanol (17 mL) was treated with 6.0 M hydrogen chloride in water (11 mL, 69 mmol) dropwise and stirred 20° C. for 30 min. The reaction mixture was added dropwise to ice cooled saturated sodium bicarbonate solution (75 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired products [from peak 1 (1.5 g, 99%); from peak 2 (1.5 g, 99%)] that were used without further purification. From peak 1: 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 4.16-3.99 (m, 1H), 3.83 (q, J=7.0 Hz, 2H), 3.65-3.54 (m, 1H), 3.30-3.23 (m, 1H), 2.55 (s, 3H), 2.33 (dd, J=16.8, 8.4 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H). LCMS for C14H16ClFNO3 (M+H)+: m/z=300.1; Found: 300.0. From peak 2: 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 4.13-4.00 (m, 1H), 3.87-3.77 (m, 2H), 3.65-3.55 (m, 1H), 3.31-3.23 (m, 1H), 2.55 (s, 3H), 2.32 (ddd, J=16.9, 8.4, 1.6 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H). LCMS for C14H16ClFNO3 (M+H)+: m/z=300.1; Found: 300.1.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[O:29][C:14]3=[CH:15][N:16]=[C:17]([C:19]4[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH:24]=4)[CH:18]=[C:13]3[CH2:12]2)[CH2:7][CH2:6]1)=[NH:4].[C:30](Cl)(=O)[CH2:31][CH2:32][CH3:33]>>[CH3:28][S:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:17]2[CH:18]=[C:13]3[CH2:12][CH:11]([CH:8]4[CH2:9][CH2:10][N:5]([C:3]5[N:4]=[C:30]([CH2:31][CH2:32][CH3:33])[O:1][N:2]=5)[CH2:6][CH2:7]4)[O:29][C:14]3=[CH:15][N:16]=2)[CH2:24][CH2:23]1)(=[O:27])=[O:26]
Reactant: CCCC(=O)Cl
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)CC1
Product: CCCc1nc(N2CCC(C3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from N-hydroxy-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl]-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxamidine and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 5): tR=1.10 min; Mass spectrum (ESI+): m/z=474 [M+H]+.