Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH:7]1[CH:12]=[C:11]2[C:13]([NH:15][C:16]([C:18]3=[CH:19][CH:20]=[CH:21][C:9](=[C:10]23)[CH:8]=1)=[O:17])=[O:14].C(Br)C#C.C(O)(=O)C>CN(C)C=O>[CH2:3]([N:15]1[C:16](=[O:17])[C:18]2[CH:19]=[CH:20][CH:21]=[C:9]3[C:10]=2[C:11](=[CH:12][CH:7]=[CH:8]3)[C:13]1=[O:14])[C:2]#[CH:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C#CCN1C(=O)c2cccc3cccc(c23)C1=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Potassium t-butoxide, 6.2 g (0.055 mol) was added to a solution of 9.9 g (0.05 mol) of naphthalimide in 50 ml of dimethylformamide cooled to -20° C. After stirring in the cold for 1 hour, 5 ml (0.055 mol) of propargyl bromide in 20 ml of dimethylformamide was added and the mixture was allowed to warm to room temperature. It was then heated to 45° C. for 45 minutes. After cooling, 15 ml of glacial acetic acid was added and the product was precipitated by addition of water. The solids were collected and recrystallized from ethyl acetate to leave 10 g (84%) of colorless crystals of 2-(2-propynyl)-1H-benz[de]isoquinoline-1,3-(2H)-dione with m.p. 235°-237° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:14]1
Reactant: Clc1ccccn1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCNc2ccccn2)CC1
Yield: 13.4 %

Procedure:
The product of Example 27 (3.9 g, 16 mmol) and 2-chloropyridine (1.82 g, 16 mmol) were heated at 160° C. in a sealed vessel for 6 h. After cooling, the residue was taken up into CH2Cl2 (50 ml) washed with aqueous NaOH (3×50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography [alumina; ethyl acetate-toluene (1:4)] to give the product (0.7 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:11][CH3:10])[CH:21]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: COC(=O)c1ccc(-c2nc(Cl)ncc2C)cc1OC
Temperature: 110 °C
Yield: 56.4 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (244 mg, 1.5 mmol) and methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (210 mg, 1.0 mmol) in toluene (3 mL) were added n-propanol (1 mL), aqueous sodium bicarbonate (2 M, 1.5 μL) and tetrakis(triphenylphosphine)palladium[0](116 mg, 0.1 mmol). The reaction was heated at 110° C. for 40 h, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions were washed with water, brine then dried (sodium sulfate), filtered and concentrated. Silica gel chromatography using 30-60% ethyl acetate/petroleum spirit as eluent provided methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate as a cream solid (165 mg, 56%); LC-ESI-MS (method B): rt 6.2 min.; m/z 293.3/295.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O1CCCC1>[O:11]1[CH2:10][CH:9]1[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: ClCC1CO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C1CCN(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperidine (3 ml) was dissolved in t-butyl alcohol (1.2 ml), and the solution was added dropwise with (±)-epichlorohydrin (2.45 ml) on an ice bath. The mixture was slowly warmed to room temperature as it was, and stirred for 18 hours. Then, the mixture was added dropwise with a solution of potassium t-butoxide (3.39 g) in tetrahydrofuran (18 ml) under ice cooling so that the internal temperature should not exceed 15° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was added to distilled water, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the title compound (1.55 g).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27]I>CN(C)C=O>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH3:27])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Sc2ccccc2C)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C#N)c1cccc(Sc2ccccc2C)c1OC
Yield: 102.2 %

Procedure:
Sodium hydride (65%, 1.05 g), ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]acetate (9.4 g), methyl iodide (7.85 g) and dimethylformamide (40 ml) were treated in a similar manner to that of Example 22-(2) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]propionate (10.0 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][O:16][CH:15]3[N:12]([C:13](=[O:23])[CH:14]3[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:11]=2[NH:24][C:25](=[O:43])[CH2:26][C:27]([O:29]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]>C(O)=O.C(O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][O:16][CH:15]3[N:12]([C:13](=[O:23])[CH:14]3[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:11]=2[NH:24][C:25](=[O:43])[CH2:26][C:27]([OH:29])=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(C2=C(NC(=O)CC(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(c4cccs4)C3OC2)s1
Solvent: O=CO
Solvent: CCO
Product: CC(=O)Nc1ncc(C2=C(NC(=O)CC(=O)O)N3C(=O)C(c4cccs4)C3OC2)s1
Yield: 16.4 %

Procedure:
A solution of 3-(2-acetylamino-thiazol-5-yl)-2-benzhydryloxycarbonyl-8-oxo-7-(thien-2-yl)-acetamido-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (0.1 g) in formic acid (5 cc) is heated at 50° C. for 30 minutes, with stirring. The mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C., and the residue is dissolved in ethanol (5 cc). The suspension obtained is stirred at 50° C. for 5 minutes and the solvent is evaporated under reduced pressure (30 mm Hg; 4 kPa) at 50° C.; this operation is repeated once, and the residue thus obtained is taken up in ethanol (2 cc). The solid in suspension yields, on filtration, 3-(2-acetylamino-thiazol-5-yl)-2-carboxy-8-oxo-7-(thien-2-yl)-acetamido-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (12 mg) in the form of a beige powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=1[CH3:21])=[O:8].[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=2[CH3:21])=[O:8])=[C:27]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:35]
Reactant: COc1c(C)c(C)c(C(=O)CCCCCBr)c(C)c1OC
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCC(=O)c2c(C)c(C)c(OC)c(OC)c2C)ccc(C(=O)OC)c1O
Yield: 83 %

Procedure:
A mixture of 0.194 g (2.6 mmol) of 6-bromo-1-(3,4-dimethoxy-2,5,6-trimethylphenyl)-1-hexanone, 0.55 g (2.6 mmol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 1.10 g (7.8 mmol) of potassium carbonate in 20 mL of acetone and 2 mL of DMF was stirred at reflux for 17 hours. After workup as in Example 16, the crude product was purified by chromatography on 100 g of silica gel. Elution with 10% ethyl acetate-hexane gave 1.05 g (83% yield) of 4-[[6-(3,4-dimethoxy-2,5,6-trimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propylbenzoic acid methyl ester. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 486 (C28H28O7).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:10]([CH2:11]O)=[CH:9][N:8]=[C:7]([C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[N:6]=1.S(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:11][C:10]1[C:5]([CH2:4][CH2:3][O:2][CH3:1])=[N:6][C:7]([C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[N:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CO
Solvent: ClCCl
Product: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CCl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.5 %

Procedure:
A cooled (0° C.) solution of 0.94 g (3 mmol) of [4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-yl]-methanol in 30 ml dichloromethane was treated with 0.44 ml (6 mmol) thionylchloride and stirred for 2.5 h at RT. The reaction was evaporated, dissolved twice in heptane an evaporated to give 1.0 g of pure 5-chloromethyl-4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[CH:9][O:10][C:11]=2[CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O.C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[CH:9][O:10][C:11]=2[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: COc1ccccc1O
Reactant: OCCCCc1ocnc1-c1ccc(Cl)s1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccccc1OCCCCc1ocnc1-c1ccc(Cl)s1
Reaction time: 1 h

Procedure:
To a mixture of 4-(5-chloro-2-thienyl)-5-oxazolebutanol (800 mg), 2-methoxyphenol (770 mg), tributylphosphine (1.24 g) and tetrahydrofuran (10 ml) was added dropwise a toluene solution of diethyl azodicarboxylate (40%, 2.61 g) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(5-chloro-2-thienyl)-5-[4-(2-methoxyphenoxy)butyl]oxazole was obtained as an oil (420 mg, 37%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)=[CH:5][N:6]2[C:11]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7]2)[CH3:2].[CH3:34][C:35](=[O:38])[C:36]#[CH:37]>>[C:35]([C:36]1[CH:37]=[C:5]2[N:6]3[C:11](=[C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:9]=[CH:8][C:7]=13)[C:3]([CH2:1][CH3:2])=[C:4]2[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:25]=1)(=[O:38])[CH3:34]
Reactant: C#CC(C)=O
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(OCc3ccccc3)c12
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3ccc(OCc4ccccc4)c1n32
Yield: 14 %

Procedure:
1-Ethyl-8-benzyloxy-2-(4-benzyloxyphenyl)indolizine was reacted with 3-butyn-2-one by the general synthetic principles outlined in example 73, step 1, to afford the title compound as yellow crystals in 14% yield. M.p. 147-149° C. MS(SP): m/z 499 (M+). 1H--NMR (DMSO-d6, 200 MHz) δ: 1.37 (t, 3 H); 2.65 (s, 3 H); 3.16 (q, 2 H); 5.22 (s, 2 H); 5.53 (s, 2 H); 7.23 (d, 2 H); 7.33-7.83 (m, 13 H); 8.13 (s, 1 H); 8.28 (d, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][CH2:13]O)([O-:3])=[O:2].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:13][CH2:12][CH2:11][NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1NCCCO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccccc1NCCCCl
Reaction time: 6 h
Yield: 100 %

Procedure:
To a stirred mixture of 39.2 parts of 3-(2-nitrophenyl)amino-1-propanol and 225 parts of trichloromethane are added dropwise 35.7 parts of sulfinyl chloride (exothermic reaction: the temperature rises to 45° C.). Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is evaporated, yielding 43 parts (100%) of N-(3-chloropropyl)-2-nitrobenzenamine as a residue.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21](CC2C=CC(OC)=CC=2)[C:22](=[O:24])[CH3:23])[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:34]1([NH2:41])[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1.O>CN1C(=O)CCC1>[C:22]([NH:21][C:4]1[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=[C:2]([NH:40][C@H:37]2[CH2:38][CH2:39][C@H:34]([NH2:41])[CH2:35][CH2:36]2)[CH:3]=1)(=[O:24])[CH3:23]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(C(C)=O)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(N-(4-methoxybenzyl)acetamido)imidazo[1,2-b]pyridazine-3-carboxamide 19B (30 mg, 0.064 mmol) and trans-cyclohexane-1,4-diamine (14.61 mg, 0.128 mmol) in NMP (0.5 mL) was heated at 70° C. for 2.5 h, and then cooled to room temperature. Water was added. The mixture was extracted with EtOAc for three times, the combined extracts were washed with H2O and brine, and then concentrated. The resulting residue was treated with MeOH. The solid was filtered off, and the filtrate was purified by preparative HPLC. The desired fraction was concentrated to dryness and then dissolved in TFA (1 mL). The solution was stirred at 70° C. for 6 h and then concentrated. The residue was treated with MeOH/DCM, and concentrated again to give a solid, which was triturated with ether. The solid was collected by filtration, rinsed with ether, and dried under vacuum to give 19C (7.3 mg, 21%) as an off white solid. [M+H]=427. HPLC Peak Rt=2.018 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([O:17][C:18]([F:27])([F:26])[CH:19]([F:25])[O:20][C:21]([F:24])([F:23])[F:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([O:17][C:18]([F:27])([F:26])[CH:19]([F:25])[O:20][C:21]([F:23])([F:24])[F:22])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1ncccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a mixture of 1.32 g of methyl 1-(3-chloro-2-pyridinyl)-3-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]-1H-pyrazole-5-carboxylate and 15 ml of methanol was added 5 ml of a 2N aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was washed with methyl tert-butyl ether. The aqueous layer was adjusted to pH 2 by an addition of 6N hydrochloric acid and then extracted with methyl tert-butyl ether two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.18 g of 1-(3-chloro-2-pyridinyl)-3-[1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy]-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH3:6].[I-].[Na+].[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])(=[O:11])[CH3:10].[H-].[Na+]>CN(C)C=O.O>[C:9]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[C:26]([NH2:32])[C:22]=3[C:23](=[O:25])[CH:24]=2)=[CH:15][C:14]=1[F:33])[CH2:2][CH2:3][CH2:4][O:5][CH3:6])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: COCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
949 mg of 1-chloro-3-methoxypropane and 1.30 g of sodium iodide were dissolved in 20 ml of dimethylformamide under argon atmosphere and the mixture was stirred at 90° C. for 2 hours. The reaction solution was cooled on ice and 1.51 g (4.35mmol) of Compound 27 obtained in Example 27 and 89 mg of sodium hydride (60% oil dispersion) were added thereto. The mixture was stirred at room temperature for 1 hour, 943 mg of 1-chloro-3-methoxypropane and 191 mg of sodium hydride (60% oil dispersion) were added, the temperature was raised to 60° C. and the mixture was stirred for 2 days. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 1.18 g (65%) of 2-[4-[N-acetyl-N-(3-methoxypropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].OS(O)(=O)=O.C1C(=O)N([Br:24])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:24][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a solution of 1-fluoro-3-methyl-2-nitro-benzene (5 g, 32.24 mmol, 1.0 eq) in TFA (25 mL) and conc.H2SO4 (10 mL) at 0° C. was added NBS (6.31 g, 35.46 mmol, 1.1 eq) in portions. After addition, the mixture was stirred at room temperature for 2 h. The resulting mixture was poured onto ice and the precipitate that formed collected by filtration, washed with water and dried in vacuo to give the title compound as a yellow solid (5 g, 67%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:21](Cl)(=[O:23])[CH3:22].Cl>C(=S)=S>[C:21]([C:12]1[CH:13]=[CH:14][C:9]2[S:8][C:7]3[CH:15]=[CH:16][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=3[C:10]=2[CH:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc2sc3ccccc3c2c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2sc3ccc(C(C)=O)cc3c2c1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
To a solution of 45.3 g of 2-dibenzothienyl methyl ketone in one liter of carbon disulfide was added 106 g of anhydrous aluminum chloride. To this was added 17.3 g of acetyl chloride over 8 minutes. This mixture was refluxed for 3 hours and then poured into a mixture of 2 liters of crushed ice and 400 ml of concentrated hydrochloride acid. This mixture was stirred until the green color had changed to pale tan, then the solid was collected washed with water and air dried. This solid was collected, washed with water and air dried. This solid was dissolved in 2 liters of hot acetontride, filtered, concentrated to about one liter and allowed to crystallize, giving 39.0 g of the desired product as tan crystals, mp 207°-210° C.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.CN1CCCC1=O.[OH-].[K+].[CH2:35]([SH:43])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].Cl>C1(C)C(C)=CC=CC=1>[CH2:35]([S:43][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCS
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: CCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 172.5 °C
Reaction time: 4.5 h

Procedure:
To a 500-mL, round-bottomed flask are charged 30 g (0.083 mol) of 5-chloro-2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole, 65 g (0.65 mol) of N-methyl-pyrrolidinone, 13.5 g (0.21 mol) of potassium hydroxide pellets and 25 g (0.16 mol) of n-octyl mercaptan are added. The mixture is agitated and the resultant slurry is heated to 170-175° C. and held at that temperature for 4.5 hours. The reaction mixture is then cooled to 120° C. at which time 150 g of xylene and 90 g of 10% aqueous hydrochloric acid are added. The brine layer is split off and the xylene phase at 90° C. is washed three times with water. Xylene is partially distilled under vacuum and then 80 g of methanol are added. The temperature of the reaction mixture is reduced to ambient temperature to induce crystallization. The yellow slurry formed is further cooled to 0-5° C. and filtered. The wetcake is washed with 100 g of cold methanol and dried to constant weight. The title compound is obtained as yellow needles in a yield of 37.7 g (97%). The structure of the product is verified by 1HNMR and mass spectroscopy.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[O:12]([CH2:30][CH2:31][C:32]1(CCO)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:41](O)(=[O:43])[CH3:42].C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[O:12]([CH2:30][CH2:31][C:32]1([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[Si:13]([C:26]([CH3:28])([CH3:27])[CH3:29])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: CC(=O)C1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 160.2 %

Procedure:
After adding 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (31 mg, 0.20 mmol) to a solution of 2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethanol (810 mg, 1.97 mmol) and iodobenzene diacetate (700 mg, 2.17 mmol) in methylene chloride (10 mL), the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine in that order and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure to obtain the title compound as a brown oil (1.29 g). This was used without purification for the following step.