Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.ClC1C=CN=C2C=C(C3N=CN(C)C=3)SC=12.I[C:28]1[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH:32]=3)[S:10][C:3]=12
Reactant: CN(CCn1cc(I)cn1)C(=O)OC(C)(C)C
Reactant: Clc1ccnc2ccsc12
Agent: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Product: CN(CCn1cc(-c2cc3nccc(Cl)c3s2)cn1)C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
Starting from the chloride 2 and following the procedure described above for the synthesis of 175 (scheme 35, example 138), but replacing 4-iodo-1-methyl-1H-imidazole with tert-butyl 2-(4-iodo-1H-pyrazol-1-yl)ethyl(methyl)carbamate, title compound 180 was obtained in 75% yield. LRMS (M+1) 393.1 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1.[C:26](Cl)([Cl:28])=[O:27]>C1(C)C=CC=CC=1>[Cl:28][C:26]([O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[CH2:8][N:9]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[O:11][C:10]1=[O:24])=[O:27]
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Temperature: 120 °C

Procedure:
A stirred suspension of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (1 g, 2.69 mmol) and BnPh3PCI (25 mg) in 1.9 molar toluene solution of phosgene (15 mL) was heated at 120° C. overnight in a sealed tube. After removal of excess phosgene, the toluene solution was rotary evaporated to dryness to afford the chlorotormate product as a white semi-solid (1.18 g).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:17]=[C:16]2[C:6]([C:7]([OH:30])=[C:8]([C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:9](=[O:18])[C:10]32[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>O>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:17]=[C:16]2[C:6]([C:7]([OH:30])=[C:8]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[C:9](=[O:18])[C:10]32[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Yield: 48.8 %

Procedure:
1,1-Dimethylethyl N-((7-trifluoromethyl-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (1.29 g, 2.82 mmol) was stirred in TFA (3 mL, 40.4 mmol) at room temperature for 25 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (550 mg). MS (m/e)=400.1 (M+H)+. Calculated for C18H16F3NO6 399.09.
Reaction SMILES: [C:1]([O-:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C(Cl)(=O)C1C=CC=CC=1.[C-:20]#[N:21].[Na+]>C1S(=O)(=O)CCC1>[C:1]([C:20]#[N:21])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O=C(Cl)c1ccccc1
Product: N#CC(=O)c1ccccc1
Reaction time: 2.5 h
Yield: 99.1 %

Procedure:
72 g (0.5 mol) of sodium benzoate were mixed with 140.6 g (1 mol) of benzoyl chloride and 80 ml of tetramethylene-sulphone and 25 g (0.5 mol) of 98% pure sodium cyanide. After a stirring time of 20 minutes, an exothermic rise in the temperature to 85° C. was observed. It was now easier to stir the mixture. The subsequent reaction time was 2.5 hours at 150°-160° C. Working up gave the following yield: 65 g (99.3% of theory) of benzoyl cyanide; melting point 34° C.
Reaction SMILES: [Br:1][C:2]1(Br)[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[C:3]1=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[C:3]=1[OH:11]
Reactant: O=C1c2sccc2CCC1(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1c(Br)ccc2ccsc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
The product from Step F (1.90 g, 6.0 mmol) was dissolved in N,N-dimethylformamide (15 mL) and added sodium carbonate (3.25 g, 30.0 mmol) and heated to 100° C. for over 1.5 hours. The suspension was then stirred for 24 hours at room temperature. The reaction was filtered over sodium sulfate and rinsed with diethyl ether (50 mL). The filtrate was acidified to pH 1 with concentrated hydrochloride acid. The organic layer was washed (2×50 mL) with water, then extracted with 5% aqueous solution of potassium hydroxide (3×50 mL). The basic aqueous solution was acidified with concentrated hydrochloric acid and extracted (3×50 mL) with diethyl ether. The combined ether extracts were dried over sodium sulfate, filtered and concentrated to give 6-bromo-benzothiophen-7-ol (1.09 g, 77% crude) as a red-brown solid: 1H NMR (500 MHz, CDCl3) δ 7.45-7.42 (m, 2H), 7.31-7.29 (m, 2H), 5.93 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH:11]=O)=[CH:6][CH:5]=2.[Cl-].[CH2:14]([O:16][CH:17]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].CN(C)C(=N)N(C)C>ClCCl>[CH2:21]([O:20][C:18](=[O:19])/[C:17](/[O:16][CH2:14][CH3:15])=[CH:11]/[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]2)[CH3:22]
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2cc(C=O)ccc2[nH]1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc2[nH]c(C)cc2c1)OCC

Procedure:
In analogy to the procedures described in preparation 1a) and 1b), 2-methyl-1H-indole-5-carbaldehyde was reacted with (1,2-diethoxy-2-oxoethyl)triphenyl phosphonium chloride in dichloromethane in the presence of tetramethyl guanidine to give (Z)-2-ethoxy-3-(2-methyl-1H-indol-5-yl)-acrylic acid ethyl ester, which was subsequently hydrogenated to yield the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH2:5]([OH:16])[C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14]O)[OH:13])[OH:11])[OH:9])[OH:7].[Sb](F)(F)(F)(F)F>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:4])[O:13][CH:12]([CH:10]2[O:11][C:6]([CH3:8])([CH3:5])[O:9][CH:8]2[CH:6]2[O:7][C:12]([CH3:14])([CH3:10])[O:16][CH2:5]2)[CH2:14][O:3]1
Reactant: CC(C)=O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: F[Sb](F)(F)(F)F
Solvent: c1ccncc1
Product: CC1(C)OCC(C2OC(C)(C)OC2C2COC(C)(C)O2)O1
Temperature: 60 °C
Reaction time: 7 h
Yield: 93.3 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-mannitol and 65 mg of antimony pentafluoride, and the mixture was refluxed with stirring in a water bath of 60° C. for 7 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, a small amount of pyridine was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 17.43 g (93.3%) of 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol. Melting point, 68.5°-70.5° C. (recrystallized from 70% ethanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])=O.[Na+].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[Pd].O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccccn1
Agent: [Pd]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C[O-]
Solvent: O
Product: c1ccc(-c2ccccn2)nc1
Yield: 51.9 %

Procedure:
2-Chloropyridine (22.7 parts), benzyltriethylammonium chloride (8.0 parts), 3% palladium on charcoal (50% paste; 4.0 parts), sodium formate (20.4 parts) and sodium hydroxide liquor (32%; 27 parts) in water (60 parts) stirred at the boil under reflux for 4 hours. Sodium formate (6.8 parts) is then added tha the mixture held at the boil under reflux for a further 24 hours. The reaction mixture is cooled and then filtered. The residue is washed with ether (75 parts) and then the filtrate extracted with ether (2 × 70 parts). The combined ether extracts are dried over anhydrous magnesium sulphate. After removal of the drying agent the ether is distilled off. The residue is distilled under vacuum and the fraction b.pt. 150°-154° C./20 mm is collected giving 8.1 parts (51.9%) of 2,2'-bipyridyl.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[S:10][C:11]([CH3:13])=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[C:11]([CH3:13])[S:10][C:6]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: CCN1Cc2cc(C)sc2C(O)C1
Reactant: Fc1cccc(Br)c1Cl
Product: CCN1Cc2cc(C)sc2C(Oc2cccc(Br)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 32) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:5]=1.[Li+].[OH-].O>O1CCOCC1>[O:21]=[C:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=1)[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid methyl ester (D7) (201 mg, 0.666 mmol) in dioxane (2 ml) was treated with LiOH (42 mg, 0.998 mmol) and water (1 ml). The reaction mixture was stirred for 2 hours at room temperature. The solvent was then evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified to pH=1. The product precipitated in the aqueous layer and was removed by filtration and dried in vacuo to D8 (128 mg) as white solid.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>ClCCl>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:9]2[S:10][CH:11]=[CH:12][C:8]=2[O:7][CH3:6])=[O:20])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccsc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2sccc2OC)cc1
Reaction time: 8 h

Procedure:
2.7 ml of tin tetrachloride were added to a solution of 2.3 g of 3-methoxy-thiophene and 3.4 g of 4-methoxybenzoyl chloride in 50 ml of dichloromethane while cooling in ice. The mixture was stirred at room temp. overnight. For workup, 75 ml of 2 hydrochloric acid were added and the mixture was extracted three times with dichloromethane. The combined organic phases were washed twice with each of 2 N sodium carbonate solution and water, and then the solvent was removed in vacuo, and the crude product was purified by column filtration (SiO2, ethyl acetate/n-heptane=1:2). The product with the molecular weight of 248.3 (C13H12O3S), MS (Cl): 249 (M+H+) was obtained.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][C:15]1[C:20]([F:21])=[C:19](F)[C:18]([N+:23]([O-:25])=[O:24])=[C:17]([F:26])[C:16]=1[F:27]>CN(C)C=O>[CH3:13][O:14][C:15]1[C:16]([F:27])=[C:17]([F:26])[C:18]([N+:23]([O-:25])=[O:24])=[C:19]([N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[C:20]=1[F:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c(F)c1F
Agent: [K]
Solvent: CN(C)C=O
Product: COc1c(F)c(F)c([N+](=O)[O-])c(N2C(=O)c3ccccc3C2=O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
4.62 g (0.025 mole) of potassium phthalimide were added to a solution of 5.41 g (0.024 mole) of 4-methoxy-2,3,5,6-tetrafluoro-1-nitrobenzene (XXXIII) in 100 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the solvent was removed by evaporation under reduced pressure, the residue was dissolved in toluene, and the solution was washed with water, dried and concentrated by evaporation under reduced pressure to give an oily substance. This oily substance was subjected to silica gel column chromatography eluted with toluene, to afford 5.07 g of 4-methoxy-2-phthalimido-3,5,6-trifluoro-1-nitrobenzene (XXXIV) as pale yellow powdery crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[NH2:21][C:22]1[N:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=1>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:23]2[C:24](=[O:28])[NH:25][CH:26]=[N:27][C:22]=2[NH:21][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: Nc1cc(=O)[nH]cn1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2nc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
500 mg (1.85 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are mixed with 308 mg (2.77 mmol) of 6-aminopyrimidin-4(3H)-one, dissolved in 10 ml of isopropanol and heated under reflux under argon for 2 days. The mixture is then concentrated and the residue is recrystallized from methanol. 341 mg (51% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6]([OH:9])=[N:5]1)(=O)C.[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br)([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:9][C:6]1[CH:7]=[CH:8][NH:4][N:5]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC(=O)n1ccc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccccc1COc1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A suspension of 1-acetyl-3-hydroxy-pyrazole (3.4 g, 27.0 mmol), 2-nitrobenzyl bromide (5.9 g, 27.3 mmol) and K2CO3 (4.0 g, 28.9 mmol) in 75 mL of 2-butanone was heated to reflux for 90 min. After cooling to room temperature, the precipitated salts were filtered off and rinsed with tert-butyl methyl ether (TBME). The filtrate was then concentrated under reduced pressure (50 mbar) and redissolved in a mixture of tetrahydrofuran (THF) and methanol (MeOH) (3:2, 50 mL). 2 mL of a 10% NaOH solution were added and the solution was stirred 60 min at ambient temperature. Then, all volatiles were removed under reduced pressure (50 mL). The residue was diluted with 20 mL of H2O and 30 mL of ethyl acetate (EtOAc). The aqueous phase was extracted with EtOAc (2×20 mL). The combined org. layers were washed with water and brine (both 30 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles and recrystallised from dichloromethane (15 mL) to give the product as yellowish crystals (5.0 g, 22.8 mmol, 84%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:17])(=[O:3])[CH3:2].[Br:18]Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([C:13]([F:16])([F:14])[F:15])[C:9]([Br:18])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cccc(C(F)(F)F)c2CC1C
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(Br)c(C(F)(F)F)c2CC1C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
To a solution of 1-acetyl-2-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-indole (0.100 g, 0.45 mmol; step A above) in acetic acid (1.0 mL) at rt was added bromine (0.035 mL; 0.68 mmol). More bromine (0.020 mL, 0.39 mmol) was added after 14 h. After another 5 h, the mixture was slowly added to sat'd NaHCO3 and extracted with Et2O (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.090 g of the title compound as a white solid: MS (ES) m/z 324 (M+2 isomer).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.OO.[ClH:11]>>[Cl:11][C:6]1[C:5]([OH:8])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cl
Agent: OO
Product: Cc1ccc(O)c(Cl)n1
Temperature: 80 °C

Procedure:
In 500 ml conc. hydrochloric acid was dissolved 50.0 g (0.46 mole) 6-methyl-3-hydroxypyridine. After heating to 80° C., 150 ml 15% hydrogen peroxide was slowly added over several hours while maintaining the reaction temperature at 80°-85°. The reaction mixture was cooled to 50° C. and concentrated under reduced pressure. The residue was brought to pH 8 by careful addition of 25% sodium hydroxide solution. This mixture was extracted with ether. The solvent was removed and the residue recrystallized one time from water and one time from benzene to provide pure 2-chloro-6-methyl-3-hydroxypyridine, mp 190°-191° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH3:14])=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:8][C:4]=2[CH:3]=1.[Br:17]Br>C(Cl)Cl>[Br:17][C:3]1[C:4]2[O:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:14])[C:5]=2[CH:15]=[CH:16][C:2]=1[OH:1]
Reactant: CCOC(=O)c1oc2cc(O)ccc2c1C
Reactant: BrBr
Solvent: ClCCl
Product: CCOC(=O)c1oc2c(Br)c(O)ccc2c1C

Procedure:
A suspension of ethyl 6-hydroxy-3-methylbenzofuran-2-carboxylate (220 mg, 1 mmole) in methylene chloride (6 ml) was treated very slowly with a solution of bromine (160 mg, 1 mmole) in methylene chloride (4 ml) and with efficient stirring.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.[NH4+].[Cl-]>CC(O)C>[N:8]1([C:5]2[N:6]=[N:7][C:2]([NH:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: Clc1ccc(N2CCOCC2)nn1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Product: COC(=O)c1ccc(CNc2ccc(N3CCOCC3)nn2)cc1
Temperature: 150 °C
Yield: 8.2 %

Procedure:
To a solution of 64 (2.0 g, 10.0 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (2.2 g, 11.0 mmol) in i-PrOH (200 mL) was added NH4Cl (2.14 g, 40.0 mmol). The reaction mixture was heated at 150° C. for 72 h and concentrated. The residue was dissolved in water and the aqueous phase was extracted with the aqueous phase was separated, treated with 1N NaOH (pH 8) and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98 to 5/95) to afford the title compound 65 (270 mg, 0.82 mmol, 8% yield). 1H NMR: (400 MHz, CDCl3) δ (ppm): 7.97 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 6.90 (d, J=9.2 Hz, 1H), 6.69 (d, J=9.2 Hz, 1H), 5.16-5.06 (bs, 1H), 4.67 (s, 2H), 3.90 (s, 3H), 3.82 (t, J=4.8 Hz, 4H), 3.41 (t, J=4.8 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](O)=[O:15])[CH:5]=[CH:4][C:3]1=2.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>O1CCCC1.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:36][CH:37]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(OCCN4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
In a manner analogous to Example 1, 52.5 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxylic acid were converted by reaction with 200 ml of thionyl chloride into the acid chloride and, after dissolution in 200 ml of tetrahydrofuran added dropwise to a solution of 48.8 g of 4-[2-(4-amino-phenoxy)ethyl)-morpholine in 400 ml of pyridine while cooling slightly. The temperature should not rise above 30° C. After stirring at room temperature for 1 hour the reaction mixture was poured on to ice-water, extracted with ethyl acetate, the organic phase was washed with ice-cold 2N hydrochloric acid, dried and evaporated. The crystalline crude product was purified by filtration over a silica gel column (eluting agent hexane/ethyl acetate 1:4, then ethyl acetate, then ethyl acetate/ethanol=1:1) and recrystallized from hexane/ ethyl acetate. There were obtained 52 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4'-(2-morpholinoethoxy)-2-naphthalenecarboxanilide in white crystals, m.p. 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=[C:12]([O:18][CH3:19])[C:11]=2[F:20])[OH:9])=[CH:6][C:5]([Cl:21])=[CH:4][N:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=[C:12]([O:18][CH3:19])[C:11]=2[F:20])=[O:9])=[CH:6][C:5]([Cl:21])=[CH:4][N:3]=1
Reactant: C=Cc1ccc(OC)c(F)c1C(O)c1cc(Cl)cnc1Cl
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C=Cc1ccc(OC)c(F)c1C(=O)c1cc(Cl)cnc1Cl
Reaction time: 8 h

Procedure:
To a stirred solution of (2,5-dichloropyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanol (11.6 g, 35.3 mmol) in CH2Cl2 (400 mL) was added MnO2 (80 g, 920 mmol). The reaction mixture was allowed to stir overnight, filtered through a pad of Celite, and concentrated to afford the title compound. LRMS (ESI) calc'd for (C15H10Cl2FNO2) [M+H]+, 326.0; found 326.0.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([CH3:40])[CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:37])([F:39])[F:38]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(S(N)(=O)=O)s4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.4 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.46 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH) to yield the title compound as an off-white solid (0.21 g, 38%). MS (ISN) 542.1 [(M−H)−]; mp 216° C.