Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:9]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:24][C:21]2[CH:20]=[CH:19][C:18]([S:15]([N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]3)(=[O:17])=[O:16])=[CH:23][CH:22]=2)=[CH:4][N:3]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Reactant: Nc1ccc(Br)cn1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1ccc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)cn1)c1ccc(Cl)cc1Cl

Procedure:
Prepared from 2-amino-5-bromopyridine and 4-(N -piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichlorophenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 11.95 (1 H, br s, NH), 8.55 (1 H, s, Ar CH ortho to 2×Cl), 8.29 (1 H, d, CH ortho to SO2NH), 7.85, 7.61, 7.54 & 7.39 (4×1 H, d, s, d & d, J 11, 10 & 11 Hz, A- & B-ring CH's) 7.73 & 7.30 (2×2 H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 3.10-3.01 (4H, m, CH2NCH2), 2.18 (3H, s, CH3), 1.79-1.68 (4 H, m, CH2CH2CH2CH2CH2), 1.60-1.48 (2 H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.48 minutes. LC/MS rt=7.19 minutes, 558/560 (MH+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:9][CH2:8][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6]1)=[O:4].C[O-].[Na+]>C1(C)C=CC=CC=1>[C:21]([O:20][C:18]([N:7]1[CH2:8][CH2:9][C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccccc1[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of (3R,4R)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (200 mg) and sodium methoxide (65 mg) in anhydrous toluene (6 mL) was heated at reflux over night. After cooling to room temperature the reaction mixture was quenched with water and concentrated in vacuo. The residue was dissolved in a mixture of 1,4-dioxane (3 mL) and 2 M aqueous sodium hydroxide solution (3 mL). After stirring at RT for 5 h the mixture was diluted with water and washed with two portions of tert-butyl methyl ether. The aqueous layer was cooled to 0° C., acidified to pH 1-2 with ice-cold 1 M aqueous KHSO4 solution and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated to give (3S,4R)-4-o-tolyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester as a white solid, MS: 318.4 ([M−H])−.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CS(C)=O>[C:13]([S:15][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH3:14]
Reactant: BrCCCCOc1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)SCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
4-Phenoxybutyl bromide (5.73 g) was dissolved in dimethyl sulfoxide, and potassium thioacetate (10.71 g) was added thereto, followed by stirring at room temperature for 18 hours. The reaction solution was subjected to partitioning between ethyl acetate and water, and the organic layer was successively washed with water and a satureted saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-acetylthio-4-phenoxybutane (Compound XIX-1, 5.53 g).
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(OC)(=O)CCCCCCC/C=C\CCCCCCCC>>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC
Yield: 16 %

Procedure:
Another possible route to produce different grade of palm diesel is by using partial vacuum fractionation of palm oil methyl esters. Under pressure of 25 Pa and temperature ranging between 145° C. to 154° C., mixture of methyl esters consisting 6.0% methyl palmitate, 8.5% methyl stearate, 69.5% methyl oleate and 16.0% methyl linoleate was obtained. This fraction of methyl esters exhibits pour point of below 0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18]4[N:22](CC5C=CC(OC)=CC=5)[CH:21]=[N:20][C:19]=4[C:13]3=[N:12][C:11]2=[O:32])=[CH:5][CH:4]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:36]=1[O:43][CH3:44]>C(O)(C(F)(F)F)=O>[CH3:33][O:34][C:35]1[C:36]([O:43][CH3:44])=[C:37]([O:41][CH3:42])[CH:38]=[CH:39][C:40]=1[C:13]12[NH:12][C:11](=[O:32])[N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:14]1=[N:15][CH:16]=[N:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=12
Reactant: COc1cccc(OC)c1OC
Reactant: COc1ccc(Cn2c3ncnc4c(ncn4Cc4ccc(OC)cc4)c-3nc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)NC3(c4ccc(OC)c(OC)c4OC)C2=NC=Nc2[nH]cnc23)cc1
Temperature: 60 °C
Yield: 80 %

Procedure:
To a stirred suspension of 3 (0.43 g, 1 mmol) in 1,2,3-trimethoxybenzene (5 mL), TFA (10 mL, dropwsie) was added. The reaction mixture was heated at 60° C. for 3 h. TFA was evaporated on rotary evaporator after the disappearance of starting material (TLC) and excess of sodium bicarbonate was added. The reaction mixture was extracted with EtOAc (30×3 mL), washed with brine, dried (anhyd. Na2SO4) and adsorbed over silica and purified through column chromatography to afford 14 as yellowish white solid (0.38 g, 80%); mp: decomposed >225° C. IR: 1734 (C═O str.), 1620, 1514, 1247 (C—O str.) cm−1. 1H NMR (400 MHz, d6-DMSO): δ=3.52 (s, 3H, OCH3), 3.69 (s, 6H, OCH3), 4.60 (dd, J=15.1, 18.3 Hz, 2H, CH2), 5.80 (J=8.7 Hz, 1H, Ar—H), 6.50 (J=8.7 Hz, 1H, Ar—H), 6.85 (d, J=8.7 Hz, 2H, Ar—H), 7.22 (d, J=8.7 Hz, 2H, Ar—H), 7.50 (s, 1H, Ar—CH═N—), 7:85 (s, 1H, Imid-H), 9.40 (brs, 1H, D2O-exchangable NH). 13C NMR (100 MHz, d6-DMSO): δ=42.9, 55.6, 56.3, 60.7, 60.8, 63.4, 106.7, 114.2, 120.0, 122.0, 122.8, 129.1, 129.9, 134.9, 137.2, 142.0, 146.0, 152.6, 154.2, 154.7, 156.6, 159.1. HRMS (FAB) Calcd for C24H24N6O5, 476.1808 (M+); observed m/z 477.1875 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:9]=1)=[O:6]
Reactant: Cc1ccc2c(c1)c(C(=O)O)cn2-c1nccc2ccccc12
Reactant: O=S(Cl)Cl
Product: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1nccc2ccccc12
Product: Cl

Procedure:
15 cm3 of thionyl chloride are added at 20° C. under an argon atmosphere to 1.27 g (3.75 mmol) of 3-carboxy-1-(isoquinol-1-yl)-5-methyl-1H-indole. After stirring at reflux for 4 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated twice with 10 cm3 of dimethoxyethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1.2 g of 3-chlorocarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole hydrochloride in the form of a yellow solid which is used directly in the following step.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>C(Cl)Cl.CO>[CH:20]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:17](=[O:19])[CH2:16][C:13]3[CH:12]=[CH:11][C:10]([N:5]4[CH:6]=[N:7][C:8]5[C:4]4=[N:3][CH:2]=[N:1][CH:9]=5)=[CH:15][CH:14]=3)=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:27][CH2:28]1)([CH3:22])[CH3:21]
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cncnc32)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cncnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-purin-9-yl-phenyl)-acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 538.1 [M+H]+; tR=2.93 min (System 1); Rf=0.12 (CH2Cl2/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([F:27])([F:26])[C:8]([F:25])([F:24])[C:9]([F:23])([F:22])[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]>[OH-].[K+]>[CH2:1]([O:5][CH2:6][C:7]([F:26])([F:27])[C:8]([F:24])([F:25])[C:9]([F:22])([F:23])[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Product: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
Subsequently, the methyl 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)benzoate was heated at reflux with 20 ml of 10% aqueous KOH for 2 hours. The resulting hydrolyzed carboxylate salt reaction product mixture was then cooled to room temperature and was acidified with concentrated (98%) sulfuric acid. The desired fluorinated benzoic acid precipitate was filtered from the aqueous solution and was washed twice with 10 ml aliquots of deionized water. The product was dried in a vacuum oven at 60° C. and a pressure of 0.2 mm Hg (0.2 torr). A total of 9.5 g of the desired 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)benzoic acid was recovered.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:30])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29].C(N([CH2:36][CH3:37])CC)C>C(Cl)Cl>[S:7]([O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:30][S:7]([C:37]1[CH:36]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCOCCOCCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A solution of 73.91 g of p-toluenesulfonyl chloride (0.389 mol) in 400 mL of methylene chloride is added dropwise with stirring over a 2.5 hrs period to 400 mL of methylene chloride containing 50 g of hexaethylene glycol (0.177 mol) and 64 mL of triethylamine (39.36 g, 0.389 mol) at 0° C. The mixture is stirred for one hr at 0° C. and heated to ambient temperature for 44 hrs. The mixture is filtered and the filtrate concentrated in vacuo. The resulting residue is suspended in 500 mL of ethyl acetate and filtered. The filtrate is concentrated in vacuo to a yellow oil which was triturated eight times with 250 mL portions of warm hexane to remove unreacted p-toluenesulfonyl chloride. The resulting oil is then concentrated under high vacuum to yield 108.12 g of a yellow oil (quantitative yield).
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C@@H:6]([CH2:16][CH2:17][CH:18]=C)[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CSC.C(N(CC)CC)C>ClCCl>[CH2:9]([O:8][CH2:7][C@@H:6]([O:5][CH3:4])[CH2:16][CH2:17][CH:18]=[O:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CCC[C@@H](COCc1ccccc1)OC
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Solvent: CCN(CC)CC
Product: CO[C@@H](CCC=O)COCc1ccccc1
Temperature: 25 °C

Procedure:
A stream of ozone was dispersed into a cold (initial T=−78° C.) stirred solution of ({[(2S)-2-methoxyhex-5-en-1-yl]oxy}methyl)benzene (40 g, 182 mmol) in dichloromethane (1800 mL) until a blue color persisted. The solution was purged with nitrogen until a clear, colorless solution was obtained. Dimethyl sulfide (67.2 mL, 908 mmol) and triethylamine (76 mL, 545 mmol) were added. The stirred mixture was allowed to warm to room temperature over 60 minutes. (A test for peroxide with wet starch-iodide paper was negative.) The mixture was concentrated under reduced pressure to provide the crude title product which was used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15]3[C:20]([NH:21][C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:37])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:12]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3N)cc12
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3NC(=O)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.7 %

Procedure:
To a stirred solution of 3-(2-dimethylaminoethyl)-5-(3-aminopyrid-2-ylamino)-1H-indole (0.157 g, 0.53 mmol) and triethylamine (74 μL, 0.54 mmol, 1.0 eq) in anhydrous tetrahydrofuran (3 mL) was added dropwise benzoyl chloride (62 μL, 0.54 mmol, 1.0 eq). The resulting reaction mixture was stirred at room temperature under nitrogen for 15 minutes. A saturated solution of sodium hydrogen carbonate (10 mL) was added, and this aqueous mixture was extracted with ethyl acetate (3×10 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residue was triturated in diethyl ether to afford the title compound (0.082 g, 39%) as an amorphous solid: 13C NMR (DMSO-d6) δ166.5, 151.9, 144.5, 134.5; 132.7, 132.5, 131.6, 128.3, 128.0, 127.2, 122.8, 119.6, 117.3, 113.3, 112.1, 110.8, 110.4, 59.9, 45.0, 23.1; LRMS (m/z, relative intensity) 399 (M+, 100), 354 (33), 249 (10), 235 (18), 204 (40), 160 (86); HRMS calculated for C24H25N5O 399.2062, found 399.2080.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=1>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:22]([O:27][CH3:28])[CH:21]=1
Reactant: COc1cc(F)ccc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: COc1cc(F)ccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 70.6 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 460 mg of 4-fluoro-2-methoxyaniline in place of the 2,4-difluoroaniline. 245 mg of N-(4-fluoro-2-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:14]([OH:16])=[O:15].[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH2:20]Br.C(OCC)(=O)C>O1CCOCC1.CN(C)C=O>[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([O:13][CH2:20][CH:19]([O:22][CH3:23])[O:18][CH3:17])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:14]([OH:16])=[O:15]
Reactant: COC(CBr)OC
Reactant: Cc1c(C(=O)O)oc2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(COc1ccc2oc(C(=O)O)c(C)c2c1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred slurry of sodium hydride (0.11 g of 60% in oil, 2.7 mmol) in p-dioxane (10 mL) was added methyl 5-hydroxybenzofuran-2-carboxylic acid (0.5 g, 2.6 mmol) and the resulting green slurry was stirred at room temperature for 15 min. To this slurry was added a solution of bromoacetaldehyde dimethyl acetal (0.5 g, 3.0 mmol) in dimethylformamide (DMF) (10 mL) and the resulting solution was heated at reflux for 15 hours. The reaction mixture was poured into ethyl acetate, washed with water, brine, the organic phased dried (Na2SO4) and concentrated in vacuo. The resulting oil was flash chromatographed on silica gel (25% ethyl acetate:hexanes) to afford the title compound as a colorless solid, (0.16 g; m.p. 74°-74° C.).
Reaction SMILES: C(C1N(C[C:15]2[CH:32]=[CH:31][C:18]3/[C:19](=[CH:28]/[C:29]#N)/[C:20]4C=CC=C[C:21]=4[CH2:22][CH2:23][C:17]=3[CH:16]=2)C2=NC(C)=CC(C)=C2N=1)C.[CH:33]([O:40]CC)([O:37][CH2:38][CH3:39])OCC.S(=O)(=O)(O)O.[CH2:48]([OH:50])[CH3:49]>C(OCC)(=O)C>[O:50]=[C:48]1[C:16]2[CH:15]=[CH:32][C:31]([C:33]([O:37][CH2:38][CH3:39])=[O:40])=[CH:18][C:17]=2[CH2:23][CH2:22][C:21]2[CH:20]=[CH:19][CH:28]=[CH:29][C:49]1=2
Reactant: CCO
Reactant: CCOC(OCC)OCC
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CCc1ccccc1C2=O
Yield: 94 %

Procedure:
[step 1] 5-Oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid (JP-B-2526005, 19.9 g, 79 mmol) and triethyl orthoformate (17.0 mL, 102 mmol) were dissolved in ethanol (130 mL), concentrated sulfuric acid (1.68 mL, 32 mmol) was added, and the mixture was stirred under reflux for 12 hr. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to give ethyl 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2-carboxylate (20.8 g, 94%).
Reaction SMILES: [Cl:1]C(=O)C(OC1C=CC=CC=1)=O.ClC(=O)[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:16]>[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:16]
Reactant: COc1ccc(OC(=O)C(=O)Cl)cc1
Reactant: O=C(Cl)C(=O)Oc1ccccc1
Agent: [Cl-]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(OC(=O)Cl)cc1

Procedure:
The decarbonylation reaction was repeated in the manner as described in Example 70, except that the amount of tetraphenylphosphonium chloride was changed as set forth in Table 11, that the phenyl chloroglyoxylate was replaced with 1.396 mmol. of 4-methoxyphenyl chloroglyoxylate (4-MeO--PCG), and that the reaction temperature and reaction period were changed as set forth in Table 11. The results are also set forth in Table 11.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=2)C.[S:38]([O-:42])([O-])(=[O:40])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:38]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][C:30]([C:34]([F:36])([F:37])[F:35])=[CH:29][N:28]=2)(=[O:42])=[O:40])[CH3:11]
Reactant: CCSc1c(-c2nc3cc(C(F)(F)F)cnc3s2)c(C(F)(F)F)nn1C
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1c(-c2nc3cc(C(F)(F)F)cnc3s2)c(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.31 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.21 g of 2-(5-ethylthio-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-6-trifluoromethylthiazolo[5,4-b]pyridine and 4 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 6 hours. A 10% aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.24 g of 2-(5-ethylsulfonyl-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-6-trifluoromethylthiazolo[5,4-b]pyridine (Compound of Present Invention (28)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:19])[F:20])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2nnnc2C(F)(F)F)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoate (1.46 g, 5.27 mmol) and an aqueous solution of sodium hydroxide (20 mL, 2M, 40 mmol) in methanol/tetrahydrofuran (20 mL/10 mL). After 2 hours, adjust the pH of the reaction mixture to about 2 using a 1M aqueous hydrochloric acid solution. Extract the reaction mixture with ethyl acetate and then dichloromethane. Dry the combined organic layers over MgSO4, filter, and evaporate in vacuo to give a the title compound: Rf =0.55 (silica gel, 85% chloroform/10% methanol/5% acetic acid).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH3:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>O>[CH:9]([C:14]1[S:13][C:12]([CH3:11])=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1)=[O:10]
Reactant: Cc1sccc1-c1ccccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1sc(C=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.166 mol (15 mL) of POCl3 was added at 0° C. to a 0.5 mol (39 mL) of DMF. At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and treated with 2-methyl-3-phenylthiophene (29 g, 0.166 mol). The resulting reaction mixture was allowed to reach room temperature and after 12 h stirring at the same temperature was heated at 80° C. for 2 days. Then it was poured into a mixture of ice and water and added of sodium acetate. The precipitate so obtained was filtered, washed with water and subsequently with hexane. The yellow powder was dried in vacuo.