Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:14].[CH3:24][C:25](C)([O-])[CH3:26].[K+].IC(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:25]([CH3:26])[CH3:24])[CH:16]=1)=[O:14]
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)I
Product: CC(C)n1cc(C(=O)OCC2CCN3CCCCC3C2)c2ccccc21
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
A solution of eq-quinolizidin-2-ylmethylindole-3-carboxylate (E9b) (320 mg, 1.08 mmole) in dry THF (15 ml) at room temperature under nitrogen was treated with potassium t-butoxide (125 mg, 1.1 mmole) and stirred for 20 minutes. The solution was then treated with 2-iodopropane (0.11 ml, 1.1 mmole) and stirred for 18 h. The reaction mixture was treated with 10% Na2CO3 solution (25 ml) and extracted with ethyl acetate (2×50 ml). The combined extracts were dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting initially with ether, then with ethyl acetate, to afford the title compound (E18) as a colourless oil (240 mg, 63%). This was converted to the hydrochloride salt mp 235°-238° C. (acetone).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[O:4][N:3]=1.[CH:22](OCC)(OCC)[O:23][CH2:24][CH3:25]>>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[O:4][N:3]=[C:2]([N:1]=[CH:22][O:23][CH2:24][CH3:25])[N:6]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nc(N)no2)cc(C(C)(C)C)c1O
Reactant: CCOC(OCC)OCC
Product: CCOC=Nc1noc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 67.4 %

Procedure:
A mixture of 0.87 g (0 03 mole) of 4-(3-amino-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol and 25 ml (22.3 g; 0.15 mole) of anhydrous triethyl orthoformate is stirred at reflux (under a nitrogen atmosphere) for 24 hours. The cooled mixture is evaporated, and the residue is distributed between 75 ml of dichloromethane and 100 ml of saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted several times with fresh dichloromethane, and the combined organic layers are washed with brine. The organic layer is dried (anhydrous sodium sulfate) and evaporated. Recrystallization of the residue from aqueous acetonitrite yields 0.70 g (67% yield) of ethyl N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,2,4-oxadiazol-3-y]methanimidoate, mp 159°-161° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:35]1[C:36]2[C:37]3[CH:50]=[CH:49][S:48][C:38]=3[C:39](=[O:47])[NH:40][C:41]=2[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>>[CH:11]1([NH:10][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[C:36]4[C:37]5[CH:50]=[CH:49][S:48][C:38]=5[C:39](=[O:47])[NH:40][C:41]=4[CH:42]=[CH:43][C:44]=3[O:45][CH3:46])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(NC1CCCC1)c1ccc(Br)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC2CCCC2)cc1
Yield: 97.3 %

Procedure:
Following General Procedure E, N-[1-(4-bromophenyl)ethyl]cyclopentanamine (600 mg, 2.3 mmol) was reacted with bis(pinacolato)diboron (410 mg, 1.6 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (250 mg, 0.81 mmol) to afford the desired product (330 mg, 97%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 7.73-7.64 (m, 2H), 7.60-7.50 (m, 2H), 7.47-7.34 (m, 3H), 6.01 (d, J=5.4 Hz, 1H), 4.57 (q, J=6.8 Hz, 1H), 3.74 (s, 3H), 3.62-3.45 (m, 1H), 2.30-2.02 (m, 2H), 1.93-1.85 (m, 2H), 1.81 (d, J=6.7 Hz, 3H), 1.77-1.51 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:10])=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Sulfur trioxide pyridine complex (800 mg, 5.0 mmol) was added to a solution of 3-[3-(2,5-dimethylphenylsulfonyloxy)-5-methylphenoxy]propanol (600 mg, 1.7 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (60 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (530 mg, 89%). 1H-NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 7.68 (s, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 6.60 (s, 1H), 6.45 (s, 1H), 6.35 (s, 1H), 4.17 (t, J=6.1 Hz, 2H), 2.85 (t, J=6.1 Hz, 2H), 2.70 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:18]N(C)CCCN=C=NCC.[OH:29][N:30]1[C:34]2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[N:30]([O:29][CH3:18])[CH3:34])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.00 g, 13.93 mmol), N,O-dimethylhydroxylanine hydrochloride (1.63 g, 16.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.94 g, 15.32 mmol) and 1-hydroxybenzotriazole (2.07 g, 15.32 mmol) were placed in a 100 mL round bottomed flask and dissolved in DMF (30 mL). Diisopropylethylamine (6.1 mL, 34.82 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by addition of water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 2.60 g (72% yield) of 3-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:11][C@:12]([CH3:25])([C:22]([OH:24])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:26](OC(=O)C)=[O:27].[O:32]1CCC[CH2:33]1>>[C:1]([NH:11][C@:12]([CH3:25])([C:22]([OH:24])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:26]=[O:27])=[C:16]([O:21][CH:33]=[O:32])[CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: C1CCOC1
Reactant: CC(=O)OC=O
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NC(=O)OCc1ccccc1)C(=O)O
Product: C[C@@](Cc1ccc(OC=O)c(OC=O)c1)(NC(=O)OCc1ccccc1)C(=O)O
Yield: 100 %

Procedure:
A solution of (S)-N-carbobenzyloxy-3-(3,4-dihydroxyphenyl)-2-methylalanine (0.35 g, 1 mmol) and acetic formic anhydride (0.36 g, 4 mmol) in anhydrous tetrahydrofuran (5 ml) is stirred 24 hours at 20°-25° under dry N2. The solvent is evaporated in vacuo and the residue is dried further at 0.1mm/25° for 2 hours. The product (A) (0.4 g, 100%) is obtained as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35](C3CCCCO3)[N:34]=[CH:33][CH:32]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.Cl.[CH3:43][O:44][C:45]([CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:46]>CC(O)C>[Cl:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15]([C:14]2[CH:29]=[C:30]([C:31]3[NH:35][N:34]=[CH:33][CH:32]=3)[C:11]([N:49]3[CH2:50][CH2:51][CH:47]([C:45]([O:44][CH3:43])=[O:46])[CH2:48]3)=[N:12][CH:13]=2)=[O:16])=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: COC(=O)C1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1
Temperature: 130 °C
Reaction time: 24 h

Procedure:
DIPEA (181 μL, 1.035 mmol) was added to a mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 36.1, 100 mg, 0.207 mmol), methyl-3-pyrrolidine carboxylate hydrochloride (44.5 mg, 0.269 mmol) and iPrOH (414 μL). in MW vial, which was flushed with argon, sealed and stirred at 130° C. for 24 h. The RM was diluted with EtOAc, treated with brine and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, n-heptane/EtOAc from 40% to 100% EtOAc) followed by preparative TLC (Silica gel, eluent EtOAc). Additional lyophilization from 1,4-dioxane afforded the title compound as a white light solid. UPLC-MS (Condition 6) tR=1.09 min, m/z=492.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.90-2.02 (m, 1H) 2.02-2.14 (m, 1H) 3.06-3.20 (m, 1H) 3.23-3.48 (m, 4H) 3.61 (s, 3H) 6.35-6.48 (m, 1H) 7.34 (d, J=8.78 Hz, 2H) 7.79-7.90 (m, 1H) 7.89 (d, J=8.80 Hz, 2H) 8.03-8.13 (m, 1H) 8.70-8.83 (m, 1H) 10.26 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].[CH3:18]I>CS(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:12])[CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:18])=[C:4]([Cl:11])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CI
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2nc(Cl)nc(Cl)c21

Procedure:
In a manner similar to Preparation A, 9.52 g of 2,6-dichloropurine, 7.65 g of potassium carbonate and 7.86 g of methyl iodide in 65 ml of dimethylsulfoxide gave 1.54 g of 2,6-dichloro-7-methylpurine and 4.7 g of 2,6-dichloro-9-methylpurine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[N:20][C:21]([CH2:24][O:25][CH3:26])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[N:20][C:21]([CH2:24][O:25][CH3:26])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(COC)nc3)cc(OC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1ccc(Oc2cc(OC)c3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of ethyl 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (2.39 g) in a mixture of tetrahydrofuran (15 mL) and ethanol (10 mL) was added 1M aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 50° C. for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid (10 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (2.28 g, 100%) as a pale yellow amorphous solid. MS 329 (MH+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:23]=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: O=C(O)c1ccccc1Nc1cccc(OCc2ccccc2)c1

Procedure:
2-(3-Benzyloxyphenylamino)benzoic acid [VII; R and R"=H, OR°=3--OCH2C6H5 ] was prepared from 2-chlorobenzoic acid and 3-benzyloxyaniline according to the procedure of Example 1(a). The green solid obtained was used directly in the next reaction.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:15])([F:14])[CH:8]([OH:13])[C:9]([F:12])(F)[F:10].[CH:16]12[CH2:22][CH:19]([CH:20]=[CH:21]1)[CH2:18][CH:17]2[C:23]([O:25][CH2:26][C:27](=[O:29])[CH3:28])=[O:24].Cl.[O:31]1CCCC1>CCCCCC>[CH:16]12[CH2:22][CH:19]([CH:20]=[CH:21]1)[CH2:18][CH:17]2[C:23]([O:25][CH2:26][C:27]([CH3:28])([OH:29])[C:9]([F:12])([F:10])[C:8]([OH:31])([OH:13])[C:7]([F:15])([F:14])[F:6])=[O:24]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C1CCOC1
Reactant: CC(=O)COC(=O)C1CC2C=CC1C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(O)(COC(=O)C1CC2C=CC1C2)C(F)(F)C(O)(O)C(F)(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
In a nitrogen atmosphere at 5° C., 100 ml of 1.6M n-butyllithium in hexane was added to a mixture of 21.7 g of 1,1,1,3,3,3-hexafluoro-2-propanol and 120 g of tetrahydrofuran. The mixture was stirred at 5° C. for 1 hour. Then a dilution of 22.8 g of 2-oxopropyl 5-norbornene-2-carboxylate in 30 g of tetrahydrofuran was added at 5° C. The mixture was stirred for 15 hours, after which dilute hydrochloric acid was added for quenching and neutralization. This was followed by conventional aqueous work-up and recrystallization from hexane for purification, collecting 24.6 g of 2-methyl-3,3,5,5,5-pentafluoro-2,4,4-trihydroxypentyl 5-norbornene-2-carboxylate (yield 58%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[CH:1]
Reactant: COC(=O)CCc1ccccc1O
Reactant: C#CCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCCCCOc1ccccc1CCC(=O)OC
Temperature: 25 °C
Reaction time: 100 h
Yield: 76.8 %

Procedure:
A mixture of 0.98 g (10 mmol) of 5-hexyn-1-ol, 1.98 g (11 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 2.88 g (11 mmol) of triphenylphosphine, 1.91 g (11 mmol) of diethyl azodicarboxylate, and 220 mL of dry tetrahydrofuran was stirred at room temperature for 100 hr and then concentrated under reduced pressure. The residue was triturated with 9:1 hexane-ether. The solid was filtered with suction and washed with the same solvent mixture. The filtrate and washes were combined and concentrated in vacuo. Flash chromatography of the residue on silica gel, eluting with 9:1 hexane-ether gave 2 g (77%) of 2-[(5-hexynyl)oxy]benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(-c2ccccc2)c(F)c1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
2,4-Difluorobiphenyl (21.2 g, 111 mmol) was dissolved in chloroform (120 mL) and chlorosulfonic acid (12.5 mL, 188 mmol) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue taken up into EtOAc (100 mL) and washed with water (3×25 mL). The organics were shaken with brine, whereupon a flocculent solid formed. This was filtered and washed with EtOAc and dried to give 2′,4′-difluorobiphenyl-4-sulfonic acid as an off-white solid (12.1 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16]Br)=[C:14]([CH3:15])[C:10]=2[C:9]([C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26](=[O:28])[CH3:27])=[C:20]([CH3:29])[CH:19]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH2:16][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[C:14]([CH3:15])[C:10]=2[C:9]([C:18]2[CH:19]=[C:20]([CH3:29])[C:21]([O:25][C:26](=[O:28])[CH3:27])=[C:22]([CH3:24])[CH:23]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CCNCC
Reactant: CC(=O)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(CBr)c(C)c23)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(C)c(OC(C)=O)c(C)c3)c2c1C
Yield: 94.9 %

Procedure:
Acetic acid 4-(9-bromo-2-bromomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester (1.21 g, 2.27 mmol) was treated with diethylamine (0.71 mL, 6.82 mmol), potassium carbonate (0.94 g, 6.82 mmol), and N,N-dimethylformamide (12.1 mL). After 1 h at room temperature the reaction mixture was poured in water (250 mL), filtered, and rinsed well with water. Air drying gave the title compound as a yellow solid (1.13 g, 94.5%): NMR (DMSO-d6): δ 8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.47 (d, 2 H), 7.13 (s, 2H), 3.73 (s, 2H), 2.58-2.52 (q, 4H), 2.40 (s, 3H), 2.16 (s, 6H), 1.61 (s, 3H), 1.02 (t, 6H); MS(EI): [M+], 1 bromine isotope pattern, 523/525; Anal. Calc. for C28H30BrNO2S: C, 64.12, H, 5.77, N, 2.67. Found: C, 63.30, H, 5.67, N, 2.55.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](OC)=O.[NH3:24]>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[O:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:16]2[C:15]=1[N:24]=[C:2]([NH2:1])[CH:3]=[CH:17]2
Reactant: COC(=O)c1cccc(O)c1
Reactant: N
Reactant: Nc1cccc2c(O)cccc12
Product: CC(CCCOc1cccc2c(N)cccc12)Oc1cccc2ccc(N)nc12

Procedure:
The title compound was prepared according to the procedure described in Example 92 substituting 5-amino-1-naphthol for methyl 3-hydroxybenzoate. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.36 (d, 1H), 7.56 (d, 1H), 7.48 (m, 2H), 7.39 (m, 2H), 7.27 (t, 1H), 7.17 (m, 1H), 7.12 (d, 1H), 6.87 (d, 1H), 6.80 (d, 1H), 4.92 (m, 1H), 4.17 (m, 2H), 2.04 (m, 4H), 1.45 (d, 3H); MS (DCI/NH3) m/z 388 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
Ethyl 2-(4′-bromobiphenyl-4-yl)-2-methylpropionate (6.2 g, 18 mmol) was dissolved in tetrahydrofuran (150 mL), and lithium aluminum hydride (0.68 g, 18 mmol) was added at 0° C., followed by stirring at the same temperature for 1.5 hours. Water was added to the reaction solution, and the insolubles were filtered with celite, followed by extraction with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.40 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (5.0 g, 16 mmol) as a white solid (yield 92%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:18][CH2:19]COC)(=O)[C:11]1C=CC=CC=1.[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH:24]1[O:26][CH2:25]1>COCCO>[C:1]([O:9][CH:24]([CH2:23][O:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[CH2:25][O:26][CH2:11][CH2:10][O:18][CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: COCCOC(=O)c1ccccc1
Solvent: COCCO
Product: COCCOCC(COc1ccc(Cl)cc1)OC(=O)c1ccccc1
Yield: 93 %

Procedure:
A reaction was conducted as described in Example 6 except that benzoic acid was replaced with the same molar amount of 2-methoxyethyl benzoate, a compound represented by formula (3) where R2 is phenyl and OZ1 is an organic group derived from 2-methoxyethanol, and PGE was replaced with the same molar amount of 4-chlorophenyl glycidyl ether. Desired 1-(4-chlorophenoxymethyl)-2-(2-methoxyethoxy)ethyl benzoate was formed in an analytical yield of 93% and isolated in a yield of 86%.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH3:10].[CH2:19]([O:21]C=O)C>>[CH2:9]([O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH:19]=[O:21])[CH3:10]
Reactant: CCOC(=O)CCCCN
Reactant: CCOC=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCNC=O

Procedure:
1.4 ml of triethylamine are added to 1.8 g of 5-aminovaleric acid ethyl ester hydrochloride in 40 ml of formic acid ethyl ester and the whole is then heated under reflux for 2 hours. The precipitate is filtered off, washed with a small quantity of formic acid ethyl ester and concentrated by evaporation under reduced pressure in a rotary evaporator. The residue is partitioned between methylene chloride and sodium bicarbonate solution, and the organic phase is then washed with brine, dried and concentrated by evaporation. The title compound is obtained in the form of an oil.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][N:13]1[C:17]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH3:12][N:13]1[C:17]([C:18]2[S:19][C:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][N:22]=2)=[CH:16][C:15]([C:23]([F:26])([F:24])[F:25])=[N:14]1
Reactant: CCOC(=O)Cl
Reactant: Cn1nc(C(F)(F)F)cc1-c1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc(-c2cc(C(F)(F)F)nn2C)s1
Reaction time: 1.5 h

Procedure:
An n-butyl lithium-n-hexane solution (1.6 M) was added to a mixture of 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole and THF at −50° C. or below, followed by stirring at −50° C. or below for 90 minutes. Ethyl chloroformate was added to the reaction solution at −20° C. or below. After stirring at −20° C. or below for 15 minutes, it was subjected to purification in the usual way to give ethyl 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylate. This was hydrolyzed with a base in the usual way to give 2-(1-methyl-3-trifluoromethyl-1-pyrazol-5-yl)thiazole-5-carboxylic acid.