Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:24][C:25]#[N:26])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)[CH:12]=2)[N:5]2[CH:27]=[CH:28][N:29]=[C:4]2[CH:3]=1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:25]([CH2:24][C:13]1([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:27]=[CH:28][N:29]=[C:4]4[CH:3]=[C:2]([CH:30]4[CH2:32][CH2:31]4)[N:7]=3)[CH:9]=[N:10]2)[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)#[N:26]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3nc(Cl)cc4nccn34)cn2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3nc(C4CC4)cc4nccn34)cn2)C1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a vial were added tert-butyl 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (Preparation N; 400 mg; 0.967 mmol), cyclopropylboronic acid (830 mg; 9.67 mmol), Pd2dba3 (177 mg; 0.193 mmol), XPHOS (92 mg; 0.913 mmol), S-Phos (79 mg; 0.913 mmol), potassium phosphate (3.87 mmol; 2M aqueous solution) and 1,4-dioxane (10 mL). The mixture was sparged with nitrogen for 15 minutes and the vial was sealed. The mixture was heated at 75° C. with stirring for 6 hours. The mixture was allowed to cool and diluted with methylene chloride (30 mL). Aqueous sodium bicarbonate solution (20 mL) was added. The phases were separated and the aqueous phase was extracted into methylene chloride (2×30 mL). The combined organic phases were dried (magnesium sulfate), filtered and concentrated under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[C:16](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxy-3-methylbenzoic acid (Matrix Scientific, 1 g) was dissolved in methanol and cooled in an ice-bath under a nitrogen atmosphere. Thionyl chloride (5 mL) was added slowly. The reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred for 16 hours. Solid sodium bicarbonate was then added to neutralize the acid and the mixture was evaporated to dryness. The residue was partitioned between ethyl acetate (75 mL and water (100 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to afford 1.0 g of product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44]>O1CCCC1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[N:1]2[CH2:40][CH2:41][CH2:42][C:43]2=[O:44])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: O=C(Cl)CCCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1c1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of Example 64A (200 mg, 0.51 mmol) and diisopropylethylamine (0.089 mL, 0.51 mmol) in tetrahydrofuran (5 mL) was stirred for about 15 minutes at ambient temperature then 4-bromobutanoyl chloride (0.059 mL, 0.51 mmol) was added. The reaction mixture was stirred for about 16 hours. The precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was taken up in acetonitrile (5 mL) and treated with diisopropylethylamine (0.089 mL, 0.51 mmol) and heated at about 60° C. for about 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with hydrochloric acid (4 N in dioxane, 5 mL) and the reaction mixture stirred at room temperature for about 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.84 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.29-7.46 (m, 5H), 5.64 (s, 2H), 3.96 (t, J=6.9 Hz, 2H), 2.56 (t, J=7.9 Hz, 2H), 2.25-2.12 (m, 2H). MS (ESI+) m/z 359 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([F:32])[C:10]=2[F:33])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:41](OC(=O)C)(=[O:43])[CH3:42]>>[C:41]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([F:32])[C:10]=2[F:33])[CH:5]=[CH:4][N:3]=1)(=[O:43])[CH3:42]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2F)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)c(F)c2F)ccn1
Temperature: 35 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (135 mg, 0.3 mmol) in acetic anhydride (6 mL) was added Et3N (0.4 mL, 2.9 mmol). The reaction mixture was stirred at 35° C. for 4 hours, then filtered, and the filter cake washed with PE (5 mL), EtOAc (5 mL) and CH3OH (2 mL) respectively to give the title compound as a beige solid (102 mg, 68.9%).
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:13])[CH:11]=[O:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>O.C(O)C.[N+]([O-])([O-])=O.[Ag+]>[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:13])[C:11]([OH:1])=[O:12])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: CC(C=O)c1ccc(-c2ccc(F)cc2)c(Br)c1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(-c2ccc(F)cc2)c(Br)c1
Reaction time: 0.25 h

Procedure:
Silver nitrate (6.8 g.) in water (8 ml.) was stirred and treated dropwise with a mixture of 13.2 N potassium hydroxide (3.04 ml.) and water (7.3 ml.). The resulting slurry was diluted with ethanol (9 ml.) and a solution of 2-(2-bromo-4'-fluoro-4-biphenylyl)propionaldehyde (5.9 g.) in ethanol (17 ml.) was added slowly. After stirring for 15 minutes, a mixture of 13.2 N potassium hydroxide (1.8 ml.) and water (1.8 ml.) was added over 1 hour, the temperature being maintained at 43°-45°C. The reaction product was then stirred at 40°C. for 30 minutes, filtered, and the filtrate distilled in vacuo to remove the ethanol. The residue was acidified with dilute hydrochloric acid, the resulting oil isolated in ether, and the extract (after conventional washing) evaporated to dryness. Recrystallisation from light petroleum b.p. 80°-100°C. gave 2-(2-bromo-4'-fluoro-4-biphenylyl)propionic acid, m.p. 129°-131°C.
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][NH:11][C:12](=[O:41])[C@@H:13]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:14][C:15](=[O:33])[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])C1C=CC=CC=1>CO.[Pd]>[C:21]([O:20][C:18]([NH:17][C@H:16]([C:15]([NH:14][C@@H:13]([C:12]([NH:11][CH2:10][C:9]([OH:42])=[O:8])=[O:41])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)O
Yield: 89.9 %

Procedure:
23.0 g (40 mmoles) of the protected tripeptide ester obtained in Step 2 above are dissolved in 40 ml of methanol, and the mixture is hydrogenated in the presence of palladium-on-carbon catalyst. At the end of the reaction the catalyst is filtered off, washed with methanol, the filtrate and the wash are combined and evaporated under reduced pressure. The residue is triturated with diethyl ether, the solid is filtered off, washed with diethyl ether and dried in a vacuum desiccator. 17.45 g (89.8%) of tert.-butoxycarbonyl-L-tyrosyl-D-phenylalanyl-glycine are obtained; m.p.: 105°-110° C., Rf13 =0.2-0.3.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:12]>C1C=CC=CC=1.CO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a stirred solution of 6-hydroxynicotinic acid (500 mg, 3.594 mmol) in benzene (8 mL) and MeOH (2 mL) was added dropwise TMSCHN2 (1.97 mL, 3.953 mmol) at 0° C., and the mixture was stirred overnight at room temp. The reaction mixture was quenched by the addition of AcOH, and the resulting mixture was concentrated in vacuo. The residue was chromatographed on silica-gel with n-hexane-EtOAc (1:3, v/v) as eluent to give 269.8 mg (49%) methyl 2-hydroxypyridine-5-carboxylate as a white crystalline powder. IR (KBr) 3062, 1657, 1654, 1612, 1435, 1300, 1113,775, 642 cm−1; 1H-NMR (400 MHz, CDCl3) δ 3.87 (s, 3H), 6.58 (d, J=9.8 Hz, 1H), 7.99 (dd, J=2.4, 9.8 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H); MS (FAB) m/z 154 (M++1); Anal. Calcd for C7H7NO3.1/4H2O: C, 53.33; H, 4.80; N, 8.89. Found: C, 53.58; H, 4.65; N, 8.87.
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:11]([CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]1)=[C:10]2[C:39]([O:41]C)=[O:40])(=[O:6])=[O:5]>CO.O>[CH3:3][S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1)[C:11]([CH2:27][N:28]1[CH2:29][CH2:30][CH:31]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:32][CH2:33]1)=[C:10]2[C:39]([OH:41])=[O:40])(=[O:6])=[O:5]
Reactant: COC(=O)c1c(CN2CCC(N3CCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCCC4)CC3)c(C(=O)O)c2c1
Temperature: 65 °C
Yield: 63.5 %

Procedure:
Potassium hydroxide (0.551 g, 9.82 mmol) was added to an orange suspension of methyl 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.13 g, 1.963 mmol) in methanol (19.63 mL) and water (6.54 mL). The mixture was heated to 65° C. Additional methanol (10 mL) was added, and the mixture was heated overnight for 22 h. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The mixture was acidified to pH 4-5 with 2N HCl. The solid was collected by filtration and dried to give 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.700 g). The filtrate was concentrated to a volume of approximately 3 mL, and the solid precipitate was collected by filtration to afford additional 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.153 g; 0.853 g total, 73% combined yield). MS (m/z) 562.2 (M+H+).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CS(O)(=O)=O>[OH:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cn2cccc(OCc3ccccc3)c2=O)cc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)Cn2cccc(O)c2=O)cc1

Procedure:
A solution of 3-benzyloxy-1-(toluene-4-sulfonylmethyl)-1H-pyridin-2-one (50 mg) from Step B in MeSO3H (1.5 mL) was stirred at room temperature for 20 min and then quenched with ice water. The solid was filtered off and washed with water. The crude product was re-dissolved in hot MeOH (1 mL) and removed un-dissolved brownish solid. The filtrate was concentrated in vacuo to give the titled compound. MS (EI) 280 (M+H)+.
Reaction SMILES: ClC[C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8](O)=[O:9])=O.COC(=O)C1C(=CC=CC=1)[NH2:20]>>[N:5]1[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[NH:20][CH:3]=1
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Reactant: COC(=O)c1ccccc1N
Product: O=c1[nH]cnc2ccccc12

Procedure:
2-Chloromethyl-3-82-methoxycarbonyl-phenyl)-4H-quinazolin-4-one (melting point: 197°-199° C., recrystallised from toluene) was prepared from N-chloroacetyl-anthranilic acid and anthranilic acid methyl ester analogously to the method in J. pr. Chem. (4) 14 (1961), 84.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:13]([NH:17][CH:18]([CH2:20][CH3:21])[CH3:19])([CH2:15][CH3:16])[CH3:14]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([N:17]([CH:18]([CH2:20][CH3:21])[CH3:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:5]
Reactant: CCC(C)NC(C)CC
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(C)N(C(=O)c1cc(Cl)cc(Cl)c1Cl)C(C)CC
Temperature: 25 °C

Procedure:
Into a 250 ml flask, provided with a reflux condenser, were introduced 10 g of 2,3,5-trichlorobenzoyl chloride in 20 ml of anhydrous C6H6, a solution of 5.3 g of di-sec.butylamine in 7 ml of anhydrous C6H6 and 5 g of triethylamine. This mass was then heated to reflux temperature for about 1 hour. Thereupon it was left to cool down to room temperature and the solvent was removed under reduced pressure in a rotating evaporator. The mass was then washed with acidulated H2O, with H2O and was then extracted with ethyl ether. The etheric extract was then dried on anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. 12.6 g of yellowing crystals of 2,3,5-trichloro-N,N-di-sec.butyl-benzamide were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11](C)=[CH:12][C:13](C)=[C:14]([CH:31]=2)[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:7]([CH3:9])[N:8]=1.COCC1NC(C2C=C(C=CC=2)C(O)=O)=C(C)N=1.COCC1NC(C2C(C)=CC(C)=C(C=2)C(O)=O)=C(C)N=1>>[CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:31]=[C:14]([CH:13]=[CH:12][CH:11]=2)[C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)=[O:16])=[C:7]([CH3:9])[N:8]=1
Reactant: COCc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1
Agent: COCc1nc(C)c(-c2cc(C(=O)O)c(C)cc2C)[nH]1
Agent: COCc1nc(C)c(-c2cccc(C(=O)O)c2)[nH]1
Product: COCc1nc(C)c(-c2cccc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 2, except 3-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)benzoic acid (compound 156.1) was used in place of 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 2.3). m/z (ES+) 415 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.Cl.[F:20][C:21]([F:27])([F:26])[C:22]1([NH2:25])[CH2:24][CH2:23]1>>[F:20][C:21]([F:27])([F:26])[C:22]1([NH:25][C:16]([C:9]2[C:10]3[CH2:11][C@@H:12]4[CH2:15][C@@H:13]4[C:14]=3[N:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[N:8]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: NC1(C(F)(F)F)CC1
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Agent: Cl
Product: O=C(NC1(C(F)(F)F)CC1)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method UU using Intermediate 4 and 1-(trifluoromethyl)cyclopropanamine hydrochloride. LCMS m/z=350.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.6, 3.2 Hz, 1H), 1.23-1.29 (m, 3H), 1.39-1.43 (m, 2H), 2.27-2.33 (m, 1H), 2.74-2.80 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.7 and 6.2 Hz, 1H), 7.31 (s, 1H), 8.42 (dd, J=2.5 and 1.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5]S([O-])(=O)=O.C[S+](C)C.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][C:21]([C:23]2([CH3:28])[CH2:25][C:24]2([F:27])[F:26])=O)=[CH:17][CH:16]=1.O>C(#N)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2([C:23]3([CH3:28])[CH2:25][C:24]3([F:26])[F:27])[CH2:4][O:5]2)=[CH:29][CH:30]=1
Reactant: CC1(C(=O)COc2ccc(Cl)cc2)CC1(F)F
Reactant: COS(=O)(=O)[O-]
Agent: C[O-]
Agent: C[S+](C)C
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1(C2(COc3ccc(Cl)cc3)CO2)CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.4 g (0.044 mol) of sodium methoxide are added to the solution of 30 ml (0.04 mol) of a 1.36-molar solution of trimethylsulphonium methylsulphate in acetonitrile, and the mixture is stirred at room temperature for 30 minutes. 5.8 g (0.022 mol) of 1-(4-chlorophenoxyacetyl)-1-methyl-2,2-difluorocyclopropane are then added, and the mixture is stirred for 16 hours at 20° C. The reaction mixture is poured into 200 ml of water and extracted using methylene chloride, and the organic phase is washed with water and concentrated. 4.3 g (GC content of 73%; 71.6% of theory) of 2-(4-chlorophenoxymethyl)-2-(2,2-difluoro-1-methylcyclopropyl)-oxirane are obtained as a viscous resin which is reacted further directly. ##STR79##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:16](=[O:19])[NH:17][N:18]=2)=[CH:10][CH:9]=1.Cl[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:17]1[C:16](=[O:19])[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:14]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)=[N:18]1)[CH3:35]
Reactant: CCOC(=O)CCl
Reactant: COc1ccc(Cn2c(-c3ccc(Cl)cc3)n[nH]c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccc(OC)cc2)c1=O

Procedure:
2.54 g (18.4 mmol) of potassium carbonate are added to 2.90 g (9.18 mmol) of 5-(4-chlorophenyl)-4-(4-methoxyphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 55A and 1.13 g (9.18 mmol) of ethyl chloroacetate in 60 ml acetonitrile and the mixture is heated under reflux overnight with stirring. It is then concentrated, the residue is partitioned between ethyl acetate and water and the aqueous phase extracted three times more with ethyl acetate. By evaporation of the organic phases, combined and dried over magnesium sulphate, 3.58 g (97% of theory) of the target compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=[O:24])[CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][OH:24])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.411 g, 1.17 mmol) in MeOH (15 mL) was added sodium borohydride (0.045 g, 1.17 mmol), and the reaction was stirred for 15 minutes at room temperature. The mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The aqueous layer was separated and extracted twice with EtOAc, and the combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:4]=2[N:3]=1>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(C(F)(F)F)cc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H]1O[C@@H](n2c(Br)nc3ccc(C(F)(F)F)cc32)[C@H](O)[C@@H]1O
Yield: 14 %

Procedure:
Starting with 2-bromo-6-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole, this compound was prepared according to general procedure III. Following two flash column chromatographic purifications on silica gel with EtOAc/hexane (3:2), a 14% yield of the title compound was obtained as a foam. 1H NMR (DMSO-d6) δ1.4 (d, 3H, Me), 3.8-3.9 (m, 1H, CH), 3.9-4.1 (m, 2H, 2×CH), 4.45 (q, 1H, CH), 5.3 (d, 1H, OH), 5.5 (d, 1H, OH), 5.91 (d,1H, CH), 7.6 (d, 1H, aromatic), 7.82 (d, 1H, aromatic), 7.9 (s, H, aromatic).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13](F)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)[CH3:7].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:6]([O:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1)[CH3:7]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NCCOC)c([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
2-Methoxy-ethylamine (1.55 mL, 17.8 mmol) was added to a stirred solution of 4-fluoro-3-nitro-benzoic acid ethyl ester (3.60 g, 16.9 mmol) and K2CO3 (4.67 g, 33.8 mmol) in 50 mL DMF. After stirring for 4 h the mixture was poured onto ice water, stirred for 10 min, filtered and dried.
Reaction SMILES: [Cl:1][SiH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>>[Cl:1][Si:2]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: C=CCCC(=O)OCc1ccccc1
Reactant: Cl[SiH](c1ccccc1)c1ccccc1
Product: O=C(CCCC[Si](Cl)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of chlorodiphenylsilane (0.49 g; 2.58 mmol) and benzyl pent-4-enoate (0.50 g; 2.58 mmol) under argon was added two drops of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 15 hours. The crude liquid was used without purification.