Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(N2C(COC(N3CCC4(CCNCC4)C3)=O)=NN=N2)=CC=1C(F)(F)F)#N.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44]([CH2:45][N:46]3[CH2:62][CH2:61][C:49]4([CH2:53][N:52](C(OC(C)(C)C)=O)[CH2:51][CH2:50]4)[CH2:48][CH2:47]3)=[N:43][N:42]=[N:41]2)=[CH:36][C:35]=1[C:63]([F:66])([F:65])[F:64])#[N:33].Cl.O1CCOCC1>>[CH2:53]1[C:49]2([CH2:61][CH2:62][N:46]([CH2:45][C:44]3[N:40]([C:37]4[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[C:35]([C:63]([F:64])([F:65])[F:66])[CH:36]=4)[N:41]=[N:42][N:43]=3)[CH2:47][CH2:48]2)[CH2:50][CH2:51][NH:52]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3nnnn3-c3ccc(C#N)c(C(F)(F)F)c3)CC2)C1
Agent: Cl
Agent: N#Cc1ccc(-n2nnnc2COC(=O)N2CCC3(CCNCC3)C2)cc1C(F)(F)F
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2nnnc2CN2CCC3(CCNC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl 8-({1-[(4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 35, 680 mg, 1.38 mmol) was treated with 4M HCl in dioxane (8 mL, 1.38 mmol) and solution was stirred at 25° C. for 1 hour.
Reaction SMILES: [OH:1][C:2]([C:18]([F:21])([F:20])[F:19])([CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:32](=[O:33])[O:31][CH2:30]2>CC(N(C)C)=O>[OH:1][C:2]([C:18]([F:21])([F:20])[F:19])([CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([CH3:9])[CH3:8])[C:3]([NH:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:32](=[O:33])[O:31][CH2:30]2)=[O:5]
Reactant: COc1ccccc1C(C)(C)CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc2c(c1)COC2=O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: COc1ccccc1C(C)(C)CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
400 mg of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeric acid is mixed in 5 ml of dimethylacetamide at 0° C. with 0.23 ml of thionyl chloride. After 30 minutes of stirring at 0° C., 390 mg of 5-aminophthalide in 2 ml of dimethylacetamide is added, and the mixture is stirred for another 4 hours at this temperature. Then, ice water is added, extracted with ethyl acetate, and after drying (Na2SO4), the crude product is chromatographed on silica gel. With hexane/ethyl acetate (50:50), the title compound is obtained in a crystalline state, flash point 134-135° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[CH2:26][C:27]([O:29]C)=[O:28])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[CH2:26][C:27]([OH:29])=[O:28])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@H]1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 75.3 %

Procedure:
A mixture of (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(methoxycarbonylmethyl)piperidine (trans isomer) (210 mg) and 1N sodium hydroxide solution (0.573 ml) in methanol (2.0 ml) was heated to reflux for 2 hours. Methanol was evaporated in vacuo and water (20 ml) was added in the residue. The solution was acidified with 1N hydrochloric acid and extracted with methylene chloride (10 ml×2). The combined extracts were washed with brine (10 ml), dried over sodium sulfate and evaporated in vacuo. The crude crystals were recrystallized from a mixture of ethyl acetate and diethyl ether to give colorless crystals of (2R)-1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-(carboxymethyl)piperidine (trans isomer) (152.7 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Br:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](O)=[O:24])[CH:19]=[CH:20][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[Br:13][C:12]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:23](=[O:24])[CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=3)[CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]([CH3:14])[CH:11]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(Br)c(-c2cccc(NC(=O)Cc3cccc(F)c3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
A mixture of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol), 3-fluorophenylacetic acid (18 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (46 mg, 0.12 mmol) were dissolved in chloroform (1.5 ml). N,N-Diisopropylethylamine (0.02 ml, 0.13 mmol) was added and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured into brine and the organic layer washed with further brine, dried over magnesium sulphate and then concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate-toluene, 1:1), giving the title compound (12 mg, 26%). Rf 0.41 (ethyl acetate-toluene, 1:1).
Reaction SMILES: [C:1]([CH:3]=[C:4]([O-:6])[CH3:5])#[N:2].[Na+].[O:8]=[C:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=O)[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.C(O)(=O)C.N1CCCCC1>ClCCl>[O:6]=[C:4]([CH3:5])[C:3](=[CH:22][C:17]1[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:8])[C:21]=2[CH:20]=[CH:19][CH:18]=1)[C:1]#[N:2]
Reactant: CC([O-])=CC#N
Reactant: O=Cc1cccc2c1-c1ccccc1C2=O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(C#N)=Cc1cccc2c1-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound from example 11A (5.21 g, 25.0 mmol) is introduced into 180 ml of dichloromethane, and the compound from example 20A (2.89 g, 27.5 mmol), acetic acid (1.72 ml, 30.0 mmol) and piperidine (0.25 ml, 2.50 mmol) are added. The mixture is stirred at the boiling point with a water trap for 4 h. Cooling to RT is followed by dilution with 30 ml of dichloromethane and washing with water (2×50 ml), the organic phase is dried over sodium sulfate and the solvent is removed in a rotary evaporator. The resulting crude product is purified by chromatography on silica gel 60 with dichloromethane as mobile phase. Combining the product fractions and removing the solvent results in 5.40 g (79% of theory) of the title compound as mixture of E/Z isomers.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C@H:16]2[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])OC(C)(C)C)[CH3:25])[CH2:18][CH2:17]2)[CH:11]=3)[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C@H:16]2[CH2:21][CH2:20][C@H:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[CH3:35])[CH3:25])[CH2:18][CH2:17]2)[CH:11]=3)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](CO[C@H]1CC[C@H](n2cc3ccc(OCCC4CC4)cc3n2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)CO[C@H]1CC[C@H](n2cc3ccc(OCCC4CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl [(1S)-2-({trans-4-[6-(2-cyclopropylethoxy)-2H-indazol-2-yl]cyclohexyl}oxy)-1-methylethyl]carbamate (1.2 g) in ethyl acetate (30 mL) was added 4M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in pyridine (10 mL), and acetic anhydride (1 mL) was added thereto at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate and water, and the solution was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated by HPLC (C18, mobile phase: ammonium hydrogen carbonate aqueous solution/acetonitrile), and water was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (153 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(N(CC)CC)C.[CH3:49][C:50](OC(C)=O)=[O:51]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][CH2:15][O:16][C:50](=[O:51])[CH3:49])([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:33])[CH3:34])[C:24]([OH:31])=[C:25]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To 4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-ethoxycarbonylmethyl-piperidine-1-carboxylic acid tert-butyl ester (Ex. 1a, 510 mg, 1 mmol) in 4 mL of THF was added dropwise 1 M LiAlH4 solution (4 mL, 4 mmol) over a period of 15 min. The reaction was stirred for 1 h and then quenched with saturated NH4Cl solution (30 mL). The mixture was extracted with Ethyl acetate (40+20 mL) and the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in 8 mL of dichloromethane. Triethylamine (300 mg, 2.9 mmol) and DMAP (10 mg) were added followed by dropwise addition of Ac2O (205 mg, 2 mmol). The reaction mixture was stirred for 3 h and then diluted with Ethyl acetate (40 mL). The mixture was washed with 1 N HCl (2×30 mL) and water (50 mL) and dried over Na2SO4. Chromatography (2-20% Ethyl acetate/hexanes) afforded 4-(2-acetoxy-ethyl)-4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (420 mg, 82%). ESI/CI-MS m/z 506 ([M−H]−).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1/[C:6](/[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[CH:7]\[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)C.[Pd]=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccc(/C(=C/CN2CCCC2)c2ncc[nH]2)cc1
Agent: O=[Pd]
Solvent: CCO
Product: Cc1ccc(C(CCN2CCCC2)c2ncc[nH]2)cc1
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A solution of (Z)-1-(imidazol-2-yl)-1-[(4-methyl)phenyl]-3-(1-pyrrolidyl)prop-1-ene (0.31 g) in absolute ethanol (40 ml) was hydrogenated over 10% palladium oxide on charcoal (0.03 g). Absorption of hydrogen was complete after 3 h. The catalyst was removed by filtration and the filtrate concentrated to a colourless oil which solidified. Recrystallisation from isopropyl acetate afforded the title compound as pale pink crystals m.p. 125°-127° (0.21 g); τ(CDCl3)2.92(4H,s,aromatic),3.09(2H,s,imidazole), ##STR42## 7.68(3H,s,--CH3), ##STR43##
Reaction SMILES: N(OCC(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([Cl:16])[CH:10]=1.S(=O)(=O)(O)O.[CH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:11]([Cl:16])[CH:10]=1
Reactant: c1ccccc1
Reactant: Nc1ccc(Br)cc1Cl
Agent: CC(C)CON=O
Agent: O=S(=O)(O)O
Product: Clc1cc(Br)ccc1-c1ccccc1
Temperature: 52.5 °C

Procedure:
Isobutyl nitrite (121 g, 1.17 mol) and cupric chloride (21.2 g, 0.16 mol) are added to a solution of 4-bromo-2-chloroaniline (200 g, 0.97 mol) in benzene (500 mL) at 60-65° C. temperature. The reaction mixture is refluxed for 2 hrs. The reaction mixture is cooled to 50-55° C. temperature and to it a solution of aqueous sulfuric acid (92 mL conc. Sulfuric acid in 453 mL demineralized water). After refluxing for 1 hr the reaction mixture is cooled to room temperature and organic layer is separated. It is treated with an aqueous solution of urea (41 g in 127 mL water) and refluxed for 1 hr. Organic layer is separated, washed with demineralized water (2×200 mL) and dried over sodium sulfate. After removing the solvent under reduced pressure the residue is fractionally distilled to get 4-bromo-2-chlorobiphenyl.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=CC=CC=3)C=CC=1.CI.[Mg].C1[C:31]2[C:22](=C[C:24]3[C:29]([CH:30]=2)=CC=CC=3)C=CC=1.[Mg].[CH3:33]C1CC=CC=1.[Co+3:39].C/C(/[O-])=C/C(C)=O>C1COCC1>[CH3:5][C:14]1[CH2:13][CH:12]=[CH:7][CH:1]=1.[CH3:33][Co:39][CH:24]1[CH:29]=[CH:30][CH:31]=[CH:22]1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: [Co+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC1=CC=CC1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: C[Co]C1C=CC=C1
Temperature: 25 °C

Procedure:
1.1 g (6.2 mMoles) of anthracene, 300 ml of THF and 0.1 ml of methyliodide are added in an inert gas atmosphere to 7.2 g (300 mMoles) of magnesium powder (particle size <0.15 mm). A yellow-green solution is formed while stirring at room temperature, orange colored magnesium anthracene precipitating therefrom after about 2 hours. The reaction mixture is treated for about 3 hours in an ultrasonic bath (as in Example 1) and then heated while stirring to 60° C. After the addition of 32.0 g (400 mMoles) of monomeric methyl cyclopentadiene, the heat source is removed and 35.6 g (100 mMoles) of solid cobalt-(III)-acetylacetonate are added over a period of 30 minutes, the reaction mixture changing color to deep red-brown with a reflux-producing heat effect (65° C.). After cooling to 23° C., the reaction mixture is filtered off from any undissolved fractions through a G-3-glass frit and the deep red-brown filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr). The residue is taken up in 500 ml of pentane and any undissolved fractions are eliminated by filtration. The clear, deep red filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr) and the residue distilled at 10-3Torr (bath temperature 80°-140° C.). 13.6 g (62.4 mMoles=62.4% of the theoretical) of η5 -methylcyclopentadienyl cobalt methylcyclopentadiene are obtained in the form of a dark red oil which solidifies at around -5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[C:11]1(=[O:15])[CH2:14][CH2:13][CH2:12]1>O1CCCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:11]1([OH:15])[CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCC1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2nccs2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of thiazole (6.59 ml, 93 mmol) in tetrahydrofuran (238 mL) was added n-butyllithium (58.0 mL, 93 mmol) dropwise. The reaction was stirred for 15 minutes, and cyclobutanone (5.0 g, 71.3 mmol) was added via syringe. The reaction was stirred for 10 minutes and was then quenched by the addition of saturated aqueous bicarbonate solution. The cold bath was removed, and the reaction was warmed to room temperature. Ethyl acetate was added, and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the subsequent step without further purification. MS ESI(+) m/z 156 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([CH:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[CH3:36][O:37][CH:38]([O:41][CH3:42])[CH2:39][NH2:40]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1[N:40]([CH2:39][CH:38]([O:41][CH3:42])[O:37][CH3:36])[CH:11]=[C:12]([CH:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: CC(C)(C)C(O)c1coc(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Reactant: COC(CN)OC
Solvent: C1CCOC1
Solvent: CCO
Product: COC(Cn1cc(C(O)C(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g) in tetrahydrofuran (1.5 ml)-ethanol (1.5 ml) was added aminoacetaldehyde dimethyl acetal (0.16 ml) and the mixture was stirred at 60° C. for 24 hr. The solvent was evaporated and purified by silica gel column chromatography (ethyl acetate:hexane=1:1-ethyl acetate) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (198 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].O>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[O:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[N:23][C:15]=2[N:14]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Nc1ncccc1C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: O=c1oc(-c2ccccc2C(F)(F)F)nc2ncccc12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mmol) is added dropwise to a solution of 2-aminonicotinic acid (2.04 g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated at 158 C for 30 min then cooled to room temperature. The reaction is poured into 200 ml of water and an oil forms which solidifies upon stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to give 2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.56 g, 60% yield) which may be used in the next step without further purification.
Reaction SMILES: Cl.Cl[C:3]1C=CC=C[C:4]=1C(OC1CNC1)C1C=CC=CC=1Cl.[N-]=C=O.[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][C:44]([CH3:47])([CH3:46])C)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>>[Cl:25][C:26]1[CH:51]=[CH:50][CH:49]=[CH:48][C:27]=1[CH:28]([O:36][CH:37]1[CH2:40][N:39]([C:41]([NH:43][CH:44]2[CH2:46][CH2:4][CH2:3][CH2:47]2)=[O:42])[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1
Reactant: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl
Agent: Cl
Agent: [N-]=C=O
Product: O=C(NC1CCCC1)N1CC(OC(c2ccccc2Cl)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,2′-dichlorobenzhydryloxy)azetidine hydrochloride (68) and the corresponding commercially available isocyanate using the procedure described for compound (69).
Reaction SMILES: IC1C=CC=CC=1S(O)(=O)=O.OOS([O-])=O.[K+].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26]>[N+](C)([O-])=O>[CH3:18][CH2:19][CH2:20][CH2:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(O)CCCC
Agent: O=S(=O)(O)c1ccccc1I
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: CCCCC(=O)CCCC
Temperature: 70 °C
Reaction time: 7.5 h

Procedure:
1.7 mg (0.006 mmol) of 2-iodobenzenesulfonic acid, prepared by Preparation Example 1, 1.11 g (1.8 mmol) of powdered Oxone (registered trademark) and 433 mg (3 mmol) of 5-nonanol were added to 3.75 ml of nitromethane, and the mixture was heated at 70° C. while being stirred for 7.5 hours. The later treatment was carried out in the same way as in Example 1, and then 5-nonanone was obtained. The yield of the obtained 5-nonanone was determined and the result is shown in Table 1.
Reaction SMILES: ClC1N=CC2N=CN(C3SC(C(OC)=O)=C(O)C=3)C=2C=1.[Cl:21][C:22]1[N:27]=[CH:26][C:25]2[N:28]([C:31]3[S:35][C:34]([C:36]([O:38][CH3:39])=[O:37])=[C:33]([OH:40])[CH:32]=3)[CH:29]=[N:30][C:24]=2[CH:23]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]([F:58])([F:57])[F:56].[Cl-].[K+]>CN(C)C=O>[Cl:21][C:22]1[N:27]=[CH:26][C:25]2[N:28]([C:31]3[S:35][C:34]([C:36]([O:38][CH3:39])=[O:37])=[C:33]([O:40][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:55]([F:56])([F:57])[F:58])[CH:32]=3)[CH:29]=[N:30][C:24]=2[CH:23]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cc(Cl)ncc32)cc1O
Agent: COC(=O)c1sc(-n2cnc3cnc(Cl)cc32)cc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cc(Cl)ncc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 557 mg of an isomeric mixture of methyl 5-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-chloro-3H-imidazo[4,5-c]pyridin-3-yl)-3-hydroxythiophene-2-carboxylate (example C2) in 25 ml anhydrous N,N-dimethylformamide were added 248 mg K2CO3 and 428 mg 1-(bromomethyl)-2-(trifluoromethyl)benzene under a nitrogen atmosphere. The reaction mixture was stirred for 12 h at room temperature, poured into 500 ml of ice water, then 40 ml of a saturated solution of KCl were added and the mixture was allowed to stand for 12 h at 0° C. The resulting solid was filtered and washed with water. The filter cake was dissolved in dichloromethane, the organic layer was washed with water, dried with MgSO4 and concentrated under vacuum. The isomeric mixture was separated and purified by flash chromatography [(Silicagel, hexane/ethylacetate (7/3 v/v)]. The separated isomers were crystallized from dichloromethane/hexane to yield compound B3a and compound B3b. The structural assignment of the regioisomers was unequivocally established by two-dimensional 1H NMR experiments (NOESY, COSY).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18](N(OC)C)=[O:19])=[N:10]2)=[C:4]([F:24])[CH:3]=1.[CH3:25][Mg+].[Br-]>C1COCC1>[C:18]([C:11]1[C:12](=[O:17])[C:13]([O:15][CH3:16])=[CH:14][N:9]([C:5]2[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][C:4]=2[F:24])[N:10]=1)(=[O:19])[CH3:25]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cc(F)c(Br)cc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(F)c(Br)cc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 1-(4-bromo-2,5-difluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (5.0 g, 12 mmol) in THF (100 mL) was added dropwise to MeMgBr (1.0 M in THF, 50 mL, 50 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with 1 M HCl aqueous solution (70 mL) at −78° C. The mixture warmed up to room temperature and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound (3.6 g, 80% yield) as a yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 2.50 (3H, s), 3.80 (3H, s), 8.03 (1H, dd, J=8.9, 6.6 Hz), 8.17 (1H, dd, J=10.0, 6.2 Hz), 8.52 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 360 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[C:4]1=O)[CH3:2].[BH4-].[Na+].Cl>CO>[CH2:1]([C:3]1[CH2:12][CH2:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH3:2]
Reactant: CCC1CCc2cc(OC)ccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1=Cc2ccc(OC)cc2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethyl-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (6.10 g, 29.9 mmol) in MeOH (70 mL) at 0° C. is added NaBH4 slowly and the mixture is stirred at RT for 30 min. Then 2M HCl solution (200 mL) is added and the mixture is stirred for 10 min before it is extracted with EtOAc and concentrated. The residue is purified to give the title compound as a clear oil: (M+H)+=189.