Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[Na].C(NC1C=CC=CC=1)=O.[K].C(NC1C=CC=CC=1)=O.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](Cl)=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:36]2[CH:37]=[CH:38][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=CNc1ccccc1
Agent: [K]
Agent: [Na]
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Reaction time: 1.5 h
Yield: 93 %

Procedure:
Into a suitable reactor is charged 64.4 parts by weight (0.45 mole) of sodium formanilide and 8.0 parts by weight (0.05 mole) of potassium formanilide to give a 90/10 ratio of the salts. In addition, there is added 23.4 parts by weight (0.193 mole) of formanilide and 60.6 parts by weight (0.385) of p-nitrochlorobenzene. The mixture is heated and stirred for 1.5 hours at 152°-160° C. The product is isolated as described in Example 1 to obtain 75.1 parts by weight or 93% yield of 4-nitrodiphenylamine. Conversion of p-nitrochlorobenzene is 98.4%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O>ClCCl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1[C@@H]1CCCC[C@H]1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 28.5 h
Yield: 74592928 %

Procedure:
To a solution of trans-3-[2-(2-hydroxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (157 ng) in 20 ml of dichloromethane was added pyridium dichromate (307 mg) and molecular sieves 4A (144 mg) at 50° C. The reaction mixture was allowed to stir at room temperature for 28.5 hours. Insoluble material was filtered off using celite and the filtrate was washed with 1N hydrochloric acid (10 ml), saturated aqueous sodium bicarbonate (10 ml), and brine (10 ml), dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (2 g) eluted with a mixture of dichloromethaneand ethyl acetate (4:1) to give 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (116.5 mg). The nmr spectrum for this compound was identical with that of the authentic sample prepared by the method described in Example 2.
Reaction SMILES: [CH3:1][O-:2].[Mg+2].C[O-].[CH2:6]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C=O.S(=O)(=O)(O)O>CO.C1(C)C=CC=CC=1.O>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:20][C:19]=1[CH:1]=[O:2]
Reactant: C[O-]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Mg+2]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 90 °C
Yield: 94.2 %

Procedure:
A solution of magnesium methoxide (292 g of 8% solution in methanol, 0.275 mol) was added over 10 minutes to a stirred solution of p-nonylphenol (55 g, 0.25 mol) in methanol (50 ml). The stirred mixture was heated to reflux temperature, the bulk of the methanol was removed by distillation, toluene (500 ml) was added and toluene:methanol azeotrope was removed by fractional distillation until the temperature of the reaction mixture rose to 100° C. The mixture was cooled to 90° C. and an agitated slurry of paraformaldehyde fine powder (26.25 g, 0.875 mol) in toluene (100 ml) was added evenly over 1 hour to the reaction mixture at 90°-100° C. with removal of volatile by-products by distillation. Stirring was continued at 100° C. for a further hour, the mixture was cooled to 45° C. and was added to a premixed solution of concentrated sulphuric acid (62.5 g, 0.875 mol) in water (1 liter). The resulting mixture was stirred at ambient temperature for 1 hour, the phases were separated and the aqueous phase was extracted with toluene (200 ml). The toluene extract was combined with the original organic phase and toluene was removed by distillation under reduced pressure to give the crude 2-hydroxy-5-nonyl benzaldehyde as a yellow oil (58.5 g).
Reaction SMILES: FC1C=CC(C=O)=CC=1.[OH-].[Na+].Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:25][C:26]([OH:28])=[O:27])[CH2:21][C:22]([OH:24])=O)=[CH:16][CH:15]=1>C(OCC)(=O)CC(C)=O.C(Cl)(=O)C.C(O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:21][C:22](=[O:24])[O:28][C:26](=[O:27])[CH2:25]2)=[CH:18][CH:19]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccc(F)cc1
Agent: Cl
Agent: O=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: CCOC(=O)CC(C)=O
Product: O=C1CC(c2ccc(F)cc2)CC(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of commercial 4-fluorobenzaldehyde (12.4 g) in ethyl acetoacetate (25.3 ml) piperidine (2 ml) was added with stirring at rt. The cloudy solution solidifies within 3 h. The yellow solid was crushed, slurried with ethanol (20 ml), collected by suction filtration, and washed with ethanol. After drying in vacuo 27 g of a faint yellowish solid (the bis-adduct of acetoacetate to the benzaldehyde) was isolated. The powdered solid was added in portions to 40% NaOH (400 g) with stirring. The resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (370 ml) to give a colourless precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-(4-fluorophenyl)glutaric acid (12.3 g) was obtained. The suspension of finely divided 3-(4-fluorophenyl)glutaric acid in acetyl chloride (20 ml) was heated to reflux with stirring for 1 h. After cooling to rt precipitation of the product is completed by addition of petrol ether (150 ml). The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to give 3-(4-fluorophenyl)glutaric anhydride (9.4 g) as colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:4][CH:3]=1.C(=O)=O.C(#N)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:38]1[CH2:41][CH2:40][CH2:39]1>ClCCl>[N:38]1([CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CC(C)(C=O)Oc1ccc(Cl)nc1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(CN1CCC1)Oc1ccc(Cl)nc1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
2-(6-Chloropyridin-3-yloxy)-2-methylpropanal [prepared according to US2012/40949 A1] (28 g, 140 mmol, Eq: 1.00) was taken up in dry dichloromethane (252 ml) and cooled to −10° C. (dry ice/acetonitrile cooling bath) under nitrogen atmosphere. Acetic acid (10.4 ml, 182 mmol) and sodium triacetoxyborohydride (41.6 g, 196 mmol) were added. Azetidine (17 ml, 252 mmol) was next added via drop-wise addition over 6 minutes, with efficient stirring. After complete addition the mixture was stirred for 5 minutes and then the cooling bath was removed and the material warmed to ambient. After 1 hour a saturated solution of aqueous sodium bicarbonate (200 ml) was added as well as dichloromethane (80 ml). The biphasic material was transferred to a separatory funnel, agitated and the organic phase was collected. This was shaken with a 5% solution of sodium bicarbonate (200 ml) and then a 50% diluted solution of brine (200 ml). The organic phase was collected and the aqueous phases were back extracted with methylene chloride (2 100 ml). The organic phase was combined, dried with magnesium sulfate, filtered and stripped. The crude remainder was purified via column chromatography (silica gel, 40 g) eluting with a 4% solution of methanol in dichloromethane to provide the desired 5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-2-chloro-pyridin (29.66 g) as a golden brown mobile oil. LC/MS calc'd for C12H17ClN2O (m/e) 240.73, obs'd 241 (M+H, ES+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=1)[CH2:10][CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13]>C([O-])([O-])=O.[K+].[K+].O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:16][CH:11]([C:12]([F:13])([F:14])[F:15])[CH2:10][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:19]=3)[C:3]=2[CH:4]=1
Reactant: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cc(F)ccc1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Fc1ccc2c(c1)N(Cc1cccc(OC(F)(F)C(F)F)c1)CC(C(F)(F)F)O2
Temperature: 145 °C
Yield: 45.2 %

Procedure:
The 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.45 mmol) product from EX-661B was dissolved in anhydrous dimethylfornamide (20 mL), and powdered K2CO3 (180 mg) was added. The mixture was stirred and heated to 145° C. for 15 h. The mixture was diluted with water (60 mL) and extracted into ether (2×40 mL), which was washed with brine and water. The ether solution was dried over anhydrous MgSO4, and the ether was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:15) to give 86.9 mg (48%) of the desired 6-fluoro-3,4-dihydro-4-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(tri-fluoromethyl)-2H-1,4-benzoxazine product as a yellow oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) δ 7.39 (t, 1H), 7.17 (m, 3H), 6.88 (m, 1H), 6.41 (m, 2H), 5.92 (tt, 1H), 4.54 (m, 1H), 4.45 (s, 2H), 3.44 (m, 2H). 19F NMR (CDCl3) δ −77.7 (d, 3F), −88.6 (m, 2F), −120.28 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C18H13F8NO2: 428.0899 [M+H]+, found: 428.0910.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:16][CH3:17].O.C([O-])([O-])=O.[K+].[K+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Cl:25][CH2:26][C:27]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[C:5]([O:16][CH3:17])[CH:6]=2)[CH2:15][CH2:14]1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 185.2 %

Procedure:
To a 3 L flask equipped with a mechanical stirrer was added 1-(4-chloro-3-methoxyphenyl)piperazine dihydrochloride (220 g, 0.73 mol, 1 equiv), CH2Cl2 (1000 mL), and water (1000 mL). The biphasic mixture was cooled to 5° C. with an ice-water bath. K2CO3 (506 g, 5 equiv) was added to the vigorously stirring solution in portions to minimize foaming. A solution of chloroacetyl chloride (124.4 g, 1.5 equiv) in CH2Cl2 (100 mL) was added dropwise from an addition funnel, while maintaining an internal temperature below 8° C. After 1 h, the cooling bath was removed, and the reaction warmed to room temperature. After an additional 1 h, the layers were partitioned. The aqueous phase was extracted with CH2Cl2 (2×300 mL), and the combined organic layers dried over 3:1 Na2SO4/K2CO3 (addition of K2CO3 helps the solution phase to become clear). After filtration, the filtrate was concentrated in vacuo, and the residue was dried for 16 h under vacuum to afford the product as an off-white solid (410 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[Cl:18].[CH2:19]([Sn](CCCC)(CCCC)C=C)[CH2:20]CC.[F-].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:19]=[CH2:20])=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[Cl:18]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a stirred solution of 2,2′,5′-trichloro-5-iodo-4-methoxybiphenyl (3.4 g, 8.3 mmol) in toluene (100 mL) at room temperature, tributyl(vinyl)stannane (3.1 g, 9.9 mmol) was added followed by Pd(PPh3)4 (2 g, 1.7 mmol). The reaction mixture was degassed and back-filled with nitrogen (several cycles) and then stirred at reflux for 16 h. The mixture was allowed to cool to room temperature, a solution of KF (1.72 g, 29.7 mmol) in H2O (10 mL) was added and then stirred for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-2% ethyl acetate/petroleum ether) to afford the desired product (2.4 g, 92% yield) as a white solid
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.COC(=O)[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][N:11]=1>>[N:11]1[CH:10]=[CH:15][CH:14]=[C:13]([O:16][C:2]2[CH2:6][CH2:5][O:4][N:3]=2)[CH:12]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: BrC1=NOCC1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-215a and I-215b were prepared in 2 steps compound from racemic compound I-21. Bromo-4,5-dihydroisoxazole I-21 was reacted with 5-hydroxy picolinic acid methyl ester using Method 5 followed by hydrolysis using the analogous conditions as in example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=418.3 m/z. Activity: B
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[OH-].[K+].[CH3:15]I>CC(C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To 5-nitroindoline (1.0 g, 6.1 mmol) in acetone (12 ml), powdered potassium hydroxide (1.7 g, 30.5 mmol, 5 eq) was added followed by the addition of methyl iodide (1.2 g, 9.1 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and water was added and the compound was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to yield 1-methyl-5-nitro-2,3-dihydro-1H-indole (1.0 g, 92%). The crude compound was used in the next stage without purification.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N>CC(=O)CC>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCC(C)=O
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
of styrene (2 mol) and 196 gs. of maleic acid anhydride were dissolved in 1600 gs. of 2-butanone, whereafter as catalyst 0.5 gs. of azo-bis-isobutyronitrile was added. The mixture was completely polymerized in a nitrogen atmosphere in a period of approx. 4 hours, while being stirred and heated at approx. 70°-80°C. The dry, solid polymer could be obtained from the solution as a white powdery substance with a melting-point above 200°C by precipitating with methanol, filtering off, rinsing out with methanol and drying.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O>[S:24]([O:1][CH:2]1[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC2(CC1)OCCO2
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Temperature: 7 °C
Reaction time: 48 h

Procedure:
A mixture of 8-hydroxy-1,4-dioxaspiro[4.5]decane (237 g, 1.5 mol) and 700 ml of pyridine was stirred at 0° C. while p-toluenesulfonyl chloride was added portion-wise. After the addition was completed the mixture was stirred for two days at 7° C. The mixture was poured into a 4-kg mixture of equal parts of ice and water with vigorous stirring. After about fifteen minutes a solid separated; this was filtered and washed with water. Dissolved the solid in CH2Cl2 and separated CH2Cl2 solution from residual water. The organic layer was dried (K2CO3 --Na2SO4), filtered and concentrated in vacuo at 36° C. The solution remaining was diluted with Skellysolve B and cooled to -75° C. with stirring. The white solid was filtered and dried in vacuo to give 435 g (92.9%), mp 65°-67.5° C. of the subtitled intermediate. IR C=C (1600), --SO2O-- (1350, 1180), C--O/S--O--C (1105, 945, 925), --SO3 -- (675); nmr (CDCl3) was in accordance with the structure assignment; mass spectrum m/e 312 (M+).
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][N:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]1([N:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N(C)C
Agent: O=Cc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)N(C)c1cccc2ccccc12
Reaction time: 6 h

Procedure:
At 160° C. and 100 mm Hg, 14 g of alpha-naphthal and 9 g of dimethyl urethane were reacted in presence of 0.7 g of anhydrous AlCl3. The reaction was continued for 6 hours, removing the methanol formed during the reaction. A 28% conversion of naphthal was obtained, with practically complete selectivity to naphthyl-methyl-urethane.
Reaction SMILES: CO[C:3]([CH3:6])([CH3:5])[CH3:4].[F:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([F:14])[CH:13]=1>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:3]([C:13]1[C:8]([F:7])=[CH:9][C:10]([OH:15])=[CH:11][C:12]=1[F:14])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(C)(C)C
Reactant: Oc1cc(F)cc(F)c1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1c(F)cc(O)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a suspension of zirconium tetrachloride (1.17 g, 5 mmol) in DCM (10 ml) was added tert-butyl methyl ether (0.44 g, 5 mmol) at 0° C. After stirring for 30 minutes at 0° C., 3,5-difluorophenol (0.65 g, 5 mmol) in DCM was placed there and the mixture was stirred for 8 hours at 60° C. The reaction was quenched with saturated sodiumbicarbonate aqueous solution followed by addition of DCM. Then, organic layer was separated, dried over magnesium sulfate, evaporated in vacuo to give the residue which was purified through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1) to furnish 4-tert-butyl-3,5-difluorophenol as colorless oil (293 mg, 31%). 1H NMR (300 MHz, CDCl3): δ 1.42 (9H, t, J=2.2 Hz), 5.22 (1H, bs), 6.32 (2H, d, J=11.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>O1CCCC1>[CH3:9][C:4]1[N:3]=[C:2]2[NH:1][C:10](=[O:11])[O:8][C:7]2=[CH:6][CH:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(O)c(N)n1
Solvent: C1CCOC1
Product: Cc1ccc2oc(=O)[nH]c2n1

Procedure:
1.24 g (10 mmol) of 2-amino-3-hydroxy-6-methylpyridine are introduced into a three-necked round-bottomed flask. The system is placed under argon. 20 ml of anhydrous tetrahydrofuran and then 2.43 g (15 mmol) of 1,1'-carbonyldimidazole are added. The mixture is heated to reflux for 6 hours. The reaction medium is evaporated. The crystals obtained are washed with water, filtered off and redissolved in hot methanol. The solution is filtered and re-evaporated.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=4)[CH2:27][CH2:26]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: Oc1ccc(C2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
DIPEA (5.84 mL, 33.54 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.99 g, 13.41 mmol) and 4-(piperidin-4-yl)phenol hydrochloride (CAS 263139-27-1, 3.01 g, 14.08 mmol) in DMF (30 mL). The resulting solution was stirred at 80° C. for 1 hour. The mixture was cooled to room temperature, evaporated to dryness and re-dissolved in DCM (200 mL). The solution was washed with water (200 mL) and saturated brine (200 mL), dried over MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 70% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (4.47 g, 92%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].CN1CCOCC1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][O:14][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 12 h

Procedure:
Combine (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (200 mg, 0.44 mmol) and N-methylmorpholine (0.97 mmol) in toluene (10 mL). Add dropwise, methanesulfonyl chloride (0.066 g, 0.57 mmol). After 12 hours, dilute with toluene (20 mL) and extract with 1M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>CS(C)=O>[O:1]=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCO
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC=O
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a mixed solution of tert-butyl (2-hydroxyethyl)carbamate (10.0 g) in dimethyl sulfoxide (50 mL) and triethylamine (12.3 g) was added sulfur trioxide pyridine complex (15.0 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was further stirred at room temperature for 3 hr, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=17:3→13:7) to give the title compound as a pale-yellow oil (yield 6.50 g, 66%).