Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([O:16]C)[CH:13]=[CH:12][C:11]=1[I:18].[Br-].Br.B(Br)(Br)Br>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[I:18]
Reactant: COc1ccc(I)c(-c2cc(OC)ccc2I)c1
Agent: Br
Agent: BrB(Br)Br
Agent: [Br-]
Solvent: ClCCl
Product: Oc1ccc(I)c(-c2cc(O)ccc2I)c1

Procedure:
The second 2,2′-dihalo-5,5′-dimethoxybiphenyl , and preferably 2,2′-diiodo-5,5′-dimethoxybiphenyl, is then demethylated under temperatures of about −78° C. to about −20° C., and preferably from about −78° C. to about −50° C., and ambient pressure, with a bromide-containing compound such as hydrogen bromide, boron tribromide, or mixtures thereof in a chlorinated solvent such as a chlorohydrocarbon including but not limited to dichloromethane to yield 2,2′-dihalo-5,5′-dihydroxybiphenyl, and preferably 2,2′-diiodo-5,5′-dihydroxybiphenyl. Boron tribromide is the preferred reactant. The concentration of the bromide-containing compound in the chlorinated solvent may range from 0.05M to about 1M, and preferably from about 0.1M to about 0.5M. The period of the demethylation reaction may depend upon the chemical structure, but will generally be from about 5 minutes to about 2 hours, and preferably from about 15 minutes to about 1 hour. The molar ratio of 2,2′-diiodo-5,5′dimethoxybiphenyl to the bromide-containing compound is about 1:3 to 1:10, and preferably about 1:2.5 to 1:5.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][CH2:12][C@H:11]([NH:27][C:28](=[O:38])[C:29]2[C:34]([OH:35])=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][N:30]=2)[C:10](=[O:39])[O:9][C@H:8]1[CH3:40])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:41](Cl)(=[O:43])[CH3:42]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][CH2:12][C@H:11]([NH:27][C:28](=[O:38])[C:29]2[C:34]([O:35][C:41](=[O:43])[CH3:42])=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][N:30]=2)[C:10](=[O:39])[O:9][C@H:8]1[CH3:40])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(=O)Cl
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.1 %

Procedure:
To a solution of (3S,6S,7R,8S)-3-(3-hydroxy-4-methoxypicolinamido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate (80 mg, 0.145 mmol) and DMAP (28.4 mg, 0.232 mmol) in CH2Cl2 (1.45 mL) was added acetyl chloride (218 μL, 0.218 mmol) slowly and the resulting mixture was stirred at room temperature for 14 h. The reaction mixture was treated with Celite®, the solvent removed under reduced pressure, and the resulting adsorbed crude material was purified by flash chromatography (SiO2, 0→100% acetone/hexanes) to afford (3S,6S,7R,8S)-3-(3-acetoxy-4-methoxypicolinamido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate as a white powder (80 mg, 93%): mp 104-108° C.; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=8.2 Hz, 1H), 8.27 (d, J=5.4 Hz, 1H), 8.01-7.94 (m, 1H), 7.88-7.81 (m, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.55-7.43 (m, 2H), 7.39 (dd, J=8.2, 7.0 Hz, 1H), 7.29 (dd, J=7.0, 1.2 Hz, 1H), 6.96 (d, J=5.4 Hz, 1H), 5.18-5.02 (m, 3H), 4.00 (dd, J=11.7, 7.4 Hz, 1H), 3.86 (s, 3H), 3.58 (d, J=4.2 Hz, 2H), 3.37 (dd, J=11.7, 7.2 Hz, 1H), 3.22 (dd, J=14.1, 3.1 Hz, 1H), 2.76-2.63 (m, 2H), 2.38 (s, 3H), 2.34-2.22 (m, 1H), 1.38 (d, J=5.7 Hz, 3H), 1.29 (d, J=3.7 Hz, 3H), 1.27 (d, J=3.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.38, 171.66, 168.84, 162.67, 159.42, 146.73, 141.03, 137.53, 134.77, 133.99, 131.98, 128.97, 127.78, 127.34, 126.01, 125.57, 125.39, 123.50, 109.95, 77.05, 74.20, 72.26, 71.84, 56.29, 51.51, 44.99, 34.38, 32.26, 20.73, 19.15, 19.08, 18.28; HRMS-ESI (m/z) [M+H]+ calcd for C32H37N2O9 expected, 593.2494. found, 593.2502.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:16]1[O:17][C:18]2[C:19]([N:26]=1)=[N:20][CH:21]=[C:22]([CH:24]=[CH2:25])[CH:23]=2>CCOC(C)=O.ClCCl.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:16]1[O:17][C:18]2[C:19]([N:26]=1)=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[CH:23]=2
Reactant: C=Cc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)oc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)oc2c1
Reaction time: 0.5 h

Procedure:
N-(4-chloro-3-(6-vinyloxazolo[4,5-b]pyridin-2-yl)phenyl)-furan-2-carboxamide (I-22) was dissolved in EtOAc/dichloromethane (1:1; 12 ml). To the solution, catalytic amount of 5 wt % Pd—C was added. The reaction was stirred under hydrogen atmosphere for 30 minutes. LCMS indicated that the reaction was complete with a formation of new peak of desired mass 368.1 (M+1). The reaction was filtered to remove palladium on carbon and the filterate wasn concentrated under reduced pressure. The crude product was purified by column chromatography to yield the desired product N-(4-chloro-3-(6-ethyloxazolo[4,5-b]pyridin-2-yl)phenyl)furan-2-carboxamide (Example 419). 1H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.73 (d, J=2.6 Hz, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.21 (d, J=1.5 Hz, 1H), 8.12-8.03 (m, 1H), 8.00 (dd, J=6.3, 7.0 Hz, 1H), 7.74 (t, J=10.6 Hz, 1H), 7.46-7.38 (m, 1H), 6.75 (dd, J=1.7, 3.5 Hz, 1H), 2.83 (q, J=7.6, 2H), 1.34-1.22 (m, 3H). LCMS M/Z=368.1 (M+1). RT=3.20: Method A.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:36]([NH:44][NH2:45])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=1>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:45][NH:44][C:36]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:43])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)c1cccnc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
A solution of the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 in dehydrated methylene chloride (14.1 mL) was cooled to 0° C. under an argon atmosphere, and isobutyl chloroformate (231.1 mg) was gradually added so that the temperature does not exceed 0° C. Then, triethylamine (185 mg) was gradually added so that the temperature does not exceed 0° C. followed by stirring for 30 minutes, thereby a mixed acid anhydride in the reaction system was prepared. To this reaction mixture was gradually added nicotinic acid hydrazide (580 mg). After the addition, the temperature was raised to room temperature, followed by stirring for 1 hour. This reaction mixture was washed with 0.5M hydrochloric acid and saturated brine, and the organic layer was dried over magnesium sulfate, and then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1-0/1, ethyl acetate/methanol=30/1) to afford 439.5 mg of the title compound as a colorless oil (yield 78.8%).
Reaction SMILES: [OH-].[K+].[Cl:3][CH:4]=[C:5]1[CH:11]=[CH:10][C:9]2[CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=[CH:15][C:8]=2[O:7][CH2:6]1.Cl>C(O)C>[Cl:3][CH:4]=[C:5]1[CH:11]=[CH:10][C:9]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)C=CC(=CCl)CO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)C=CC(=CCl)CO2
Yield: 63.4 %

Procedure:
145 mg (2.6 mmol) of potassium hydroxide pellets are added to 0.5 g (2 mmol) of methyl 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 32, in solution in 8 ml of 80% aqueous ethanol, and the medium is brought to reflux for 3 hours. After cooling, the medium is brought to acidity by addition of 1N hydrochloric acid. The precipitate is filtered off and then washed with diisopropyl ether to provide 300 mg (63%) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylic acid in the form of a white solid comprising two Z/E isomers as a mixture in an 85/15 ratio; M.p.>260° C.
Reaction SMILES: N#N.[F:3][C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:5]=1F.C([Mg][Br:18])C.BrBr.Cl>C(Cl)Cl.C1COCC1>[C:5]1([Br:18])[C:6]([F:13])=[C:7]([F:12])[C:8]([F:11])=[C:9]([F:10])[C:4]=1[F:3]
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: CC[Mg]Br
Agent: BrBr
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1c(F)c(F)c(Br)c(F)c1F
Yield: 83 %

Procedure:
In a 2 l, N2 purged flask were combined hexafluorobenzene (145 g), FeCl2 (0.8 g) and THF (600 ml). The solution was cooled to 0°-5° C., and ethyl magnesium bromide (3.12M in Et2O, 500 ml) was then added dropwise. After the addition was complete, the reaction mixture was stirred for one-half hour. A solution of bromine (125g) n methylene chloride (250 ml) was then added dropwise to the cold (0°-5° C.) reaction mixture. After stirring 15 minutes, 4N HCl was added until all solids were dissolved. The two phases were separated and the organics were washed sequentially with water, aqueous sodium bicarbonate and brine. After drying over sodium sulfate, the mixture was distilled providing 160 g of C6F5Br (83% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12](=[O:14])[C:5]2[C:6]([C:9]([OH:11])=O)=[CH:7][O:8][C:4]=2[CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[N:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9]([C:6]2[C:5]3[C:12](=[O:14])[CH2:13][CH:2]([CH3:1])[CH2:3][C:4]=3[O:8][CH:7]=2)=[O:11])=[CH:17][CH:18]=1
Reactant: Nc1ccncc1
Reactant: CC1CC(=O)c2c(C(=O)O)coc2C1
Product: CC1CC(=O)c2c(C(=O)Nc3ccncc3)coc2C1

Procedure:
Starting from 6-methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid and 4-aminopyridine, General Procedure B provided the title compound:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>ClCCl>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:13]([C:8]1[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=1)=[O:14]
Reactant: O=C(Br)CBr
Reactant: Cc1onc(C(=O)c2c(F)cccc2F)c1N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1onc(C(=O)c2c(F)cccc2F)c1NC(=O)CBr

Procedure:
Bromoacetyl bromide (44 g, 222 mmoles) was added slowly to a mixture of (4-amino-5-methylisoxazol-3-yl)-2,6-difluorophenylmethanone of Example XIIIc (48 g, 202 mmoles) in dichloromethane (400 ml) with 2N sodium carbonate (125 ml) and saturated sodium chloride, dried (sodium sulfate) and evaporated to give 72 g of an oil. The residue (3.0 g) was flash chromatographed (25% ethyl acetate:hexane) to yield 2.3 g (77%) of a solid, melting point 76°-80° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[OH-].[Na+].Cl.[F:17][C:18]([F:23])([F:22])[CH2:19][O:20][NH2:21]>CO.O>[F:17][C:18]([F:23])([F:22])[CH2:19][O:20][N:21]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: NOCC(F)(F)F
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)O)cs1
Yield: 54.6 %

Procedure:
A suspension of 2-(2-formylaminothiazol-4-yl)-glyoxylic acid (3.0 g) in methanol (60 ml) and water (60 ml) was adjusted to pH 8 with 1 N aqueous solution of sodium hydroxide under stirring. To the solution was added 2,2,2-trifluoroethoxyamine hydrochloride (2.24 g) and then adjusted to pH 2.5 to 3 with 1 N aqueous solution of sodium hydroxide. After the solution was stirred at ambient temperature for 1.5 hours, methanol was removed from the resultant solution under reduced pressure. The remaining aqueous solution was adjusted to pH 7 with 1 N aqueous solution of sodium hydroxide and then washed with ethyl acetate. To the aqueous solution was added ethyl acetate and then adjusted to pH 1.5 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated under reduced pressure to give 2-(2,2,2-trifluoroethoxyimino)-2-(2-formylaminothiazol-4-yl)acetic acid (syn isomer) (2.4 g), mp 162° to 163° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>[OH-].[Na+]>[Cl:12][C:11]1[CH:10]=[C:9]2[C:4](=[CH:3][C:2]=1[NH:1][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:5]=[C:6]([OH:14])[C:7]([OH:13])=[N:8]2
Reactant: Nc1cc2nc(O)c(O)nc2cc1Cl
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Nc1cc2nc(O)c(O)nc2cc1Cl
Reaction time: 1 h
Yield: 9792.4 %

Procedure:
A solution of 10 g (47,3 mmol) 6-amino-7-chloro-2,3-dihydroxyquinoxaline in 200 ml 0,5N sodium hydroxide was ice-cooled, and then 30 ml (0,36 mmol) ethyl chloroformate was added. Stirring was continued at 0° C. for 1 h and at 25° C. for 1 h. To the reaction mixture was added 1N hydrochloric acid to pH 2-3, and the precipitated product was filtered off and washed with water to give 12 g of a crude product. Recrystallization (dimethylsulfoxide-0,5N hydrochloric acid) gave 10 g (75%) 6-chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline, m.p.>300° C. NMR (DMSO-d6) 11.9 (2H, broad s), 8.9 (1H, broad s), 7.37 (1H,s), 7.17 (1H,s), 4.1 (2H,q), 1.28 (3H,t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]#[N:11])=[C:4]([CH3:13])[CH:3]=1.Cl.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][NH2:23]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:11])[N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:15])[N:23]=2)=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=O)CC#N
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N)n(-c2ccccc2C)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
To a solution of 3-(4-fluoro-2-methylphenyl)-3-oxopropanenitrile (2.0 g, 11.3 mmol) in toluene (10 mL) was added (2-methylphenyl)hydrazine hydrochloride (2.15 g, 13.5 mmol). The reaction was stirred at 110° C. for 16 h, and then cooled to rt. It was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (2:1-1:1=hexanes:ethyl acetate) to afford the product as a yellow oil (500 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 3H), 2.44 (s, 3H), 5.74 (s, 1H), 7.02-7.14 (m, 2H), 7.34-7.43 (m, 4H), 7.52 (dd, 1H); ES-MS m/z 282.4 (MH+); HPLC RT (min) 3.36
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].Cl>N1C=CC=CC=1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C#N)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(CCC#N)cc1OC
Temperature: 100 °C
Yield: 80.9 %

Procedure:
To a solution of 1 g (5.3 mmoles) of (2E)-3-(3,4-dimethoxyphenyl)prop-2-enenitrile in 9.3 mL of pyridine and 2.8 mL of methanol there is added, little by little, 0.24 g of NaBH4 (6.3 mmol, 1.2 eq.). The reaction mixture is heated at reflux (100° C.) for 9 hours. After cooling to ambient temperature, the reaction mixture is added to a solution of 9 mL of hydrochloric acid 37% in 24 g of ice. The solution is extracted twice with dichloromethane. The organic phases are collected and the solvent is evaporated off under reduced pressure to yield 0.82 g of a red-brown oil which crystallises.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7])[CH3:2].CN(C=O)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH3:13])[C:11]([OH:12])=[C:3]([CH2:1][CH3:2])[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)OCc2ccccc2)cc(C)c1O
Temperature: 50 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzoic acid (80.3 g, 0.446 mol) is DMF (500 mL), KHCO3 (53.5 g, 0.535 mol) followed by benzylbromide (114.3 g, 0.668 mol) is added. The mixture is stirred at 50° C. for 18 h before it is cooled to rt, diluted with water (250 mL), and extracted with TBME (2×250 mL). The org. extracts are washed with water, and then concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 19:1 to 9:1 to give 3-ethyl-4-hydroxy-5-methyl-benzoic acid benzyl ester (108.5 g) as a beige solid; 1H NMR (CDCl3): δ1.28 (t, J=7.5 Hz, 3H), 2.30 (s, 3H), 2.68 (q, J=7.8 Hz, 2H), 5.24 (s, 1H), 5.37 (s, 2H), 7.33-7.45 (m, 3H), 7.45-7.50 (m, 2H), 7.77 (s, 1H), 7.79 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.[CH:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CC(N(C)C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:3]=[C:2]([NH:1][C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:32])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:9]2
Reactant: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2)C1CCCCC1
Reaction time: 8 h
Yield: 10.2 %

Procedure:
1-[7-amino-5-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (71 mgs, 0.2 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) to which was added cyclohexyl carbonyl chloride (40 ul, 0.3 mmoles) followed by triethylamine (41.6 ul, 0.3 mmoles) and the solution flushed with nitrogen and left stirring overnight. The product was purified by semi-preparative C18 HPLC (9.4 mgs, 10.2% yield, 100% pure, CO-AAW00031).
Reaction SMILES: [C:1]1([S:7]([C:10]([C:13]([S:16](F)(=[O:18])=[O:17])([F:15])[F:14])([F:12])[F:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>ClCCCl>[CH2:20]([NH:27][S:16]([C:13]([F:15])([F:14])[C:10]([S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])([F:12])[F:11])(=[O:18])=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Product: O=S(=O)(NCc1ccccc1)C(F)(F)C(F)(F)S(=O)(=O)c1ccccc1

Procedure:
Added to a solution of 1,2-dichloroethane (5 ml), containing the PhSO2CF2CF2SO2F (325 mg, 1 mmol) prepared according to the method from example 4, was freshly distilled benzylamine (550 μl, 5 mmol). The mixture was stirred and heated at 50° C. for 20 h until the disappearance of PhSO2CF2CF2SO2F (monitored by TLC and 19F NMR/CDCl3). After returning to ambient temperature, an aqueous solution of HCl (10%) was added to the reaction medium. The aqueous and organic phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over MgSO4. After filtration and evaporation of the solvents, the residue was purified by chromatography over silica gel (pentane to pentane/AcOEt:4/1). The sulfonamide product was obtained in the form of a white solid (340 mg, 83%).
Reaction SMILES: Cl.CN([CH2:5][CH:6]1[C:11](=[O:12])[CH:10]=[C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[I:21])[CH2:8][CH2:7]1)C.[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1>CN(C)C=O>[I:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:9]1[CH2:8][CH2:7][CH:6]([CH2:5][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH3:22])[C:11](=[O:12])[CH:10]=1
Reactant: CN(C)CC1CCC(NCc2ccccc2I)=CC1=O
Reactant: Cc1ncc[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CCC(NCc2ccccc2I)=CC1=O
Yield: 43.7 %

Procedure:
A mixture of the product of Stage (ii) (350 mg) and 2-methylimidazole (350 mg) in dry dimethylformamide (25 ml) was heated at 100° under nitrogen for 24 h. The cooled reaction mixture was evaporated in vacuo and purified by flash chromatography (C) to give, as the second eluted major component, the title compound (153 mg) as a gum. T.l.c. (C), Rf 0.35
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1.CCCCCC.C(O[CH:24](OCC)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)C>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH:24]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[N:14]=[CH:13][O:12][N:11]=1
Reactant: CCOC(OCC)c1ccc(OC)c(OC)c1
Reactant: Nc1ccccc1SCc1ncon1
Solvent: CCCCCC
Product: COc1ccc(C=Nc2ccccc2SCc2ncon2)cc1OC

Procedure:
A solution of 3-(2-aminophenylthiomethyl)1,2,4-oxadiazole (4.2 g) in 3,4-dimethoxybenzaldehyde diethyl acetal (9.6 g) was heated under reflux for 30 minutes. On cooling and the addition of hexane yellow crystals precipitated. These were removed by filtration and re-crystallised from ethanol to give 3-[2-(3,4-dimethoxybenzylideneamino)phenylthiomethyl]-1,2,4-oxadiazole, m.p. 146°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][N:26]=[C:25]2[SH:29])=[C:20]([CH3:30])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][C:20]1[CH:19]=[C:18]([Br:17])[CH:23]=[CH:22][C:21]=1[N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[S:29][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(OCCCCl)ccc2N1
Reactant: Cc1cc(Br)ccc1-n1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1-n1ccnc1SCCCOc1ccc2c(c1)CCC(=O)N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
In 300 ml of dimethylformamide were dissolved 89 g of 6-(3-chloropropoxy)-3,4-dihydrocarbostyril and 110 g of 1-(4-bromo-2-methylphenyl)-2-mercaptoimidazole. To the solution was slowly added 66.7 g of potassium carbonate at room temperature. The mixture was stirred at 80° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate. The oily layer was washed with water thoroughly, washed with an aqueous solution saturated with sodium chloride, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The resulting brown oil was purified by a silica gel column chromatography (eluant: chloroform/methanol=50/1). The resulting crude crystals were recrystallized from ethanol to obtain 118 g of 6-{3-[1-(2-methyl-4-bromophenyl)-2-imidazolylthio]propoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N+:15]=1[O-].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][C:19]([CH3:20])=[C:14]([C:4]2[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC(F)(F)F)ccc1-c1c(C)cc([N+](=O)[O-])c[n+]1[O-]
Product: COc1cc(OC(F)(F)F)ccc1-c1nc(Cl)c([N+](=O)[O-])cc1C
Temperature: 75 °C
Reaction time: 2 h

Procedure:
POCl3 (500 ml) is added to 2-(2-methoxy-4-trifluoromethoxy-phenyl)-3-methyl-5-nitro-pyridine 1-oxide (97 g, 0.3 mol) at room temperature and the mixture is stirred at 75° C. for 2 hours. The mixture is concentrated under reduced pressure. Aqueous saturated Na2CO3 is added to the residue and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure. The residue is purified by flash column chromatography (hexane/EtOAc 10:1) to obtain 2-chloro-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine. Rf (hexane/EtOAc=9:1)=0.35.