Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].C(NC(C)C)(C)C.[Li].F[B-](F)(F)F.[CH+:17]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=[CH:18]1>O1CCCC1>[CH:22]1([CH2:2][C:1]#[N:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=[CH:23]1
Reactant: CC#N
Reactant: c1ccc[cH+]cc1
Agent: F[B-](F)(F)F
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CCC1C=CC=CC=C1
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a solution of anhydrous acetonitrile (3.12 mL, 56.2 mmol, 1 eq.) in tetrahydrofuran (281 mL, 0.2 M) was added lithium diisopropylamine (1.8 M in heptane/ethylbenzene/tetrahydrofuran, 31.2 mL, 56.2 mmol, 1 eq.) at −78° C. After 20 minutes at −78° C., tropylium tetrafluoroborate (10 g, 56 mmol, 1 eq.) was added. After 10 minutes, the reaction was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide a brown oil, which was purified by silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) to provide #61 (1.88 g, 25%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.69-6.71 (m, 2H), 6.27-6.32 (m, 2H), 5.28-5.33 (m, 2H), 2.61 (d, J=7.2 Hz, 2H), 2.26-2.34 (m, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].O>CO.C1COCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(C)o4)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nnc(-c2ccc3[nH]cc(-c4cccc(OC(C)C)n4)c3c2)o1
Temperature: 45 °C
Yield: 22.9 %

Procedure:
2-(3-(6-Isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-methyl-1,3,4-oxadiazole (214 mg, 0.438 mmol) in a round bottomed flask was dissolved in MeOH (1.500 mL) and THF (3.0 mL). Cesium carbonate (428 mg, 1.314 mmol) (Aldrich) was added, the flask was fitted with a reflux condenser and the contents of the flask were heated at 45° C. for 15 min. H2O (30 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried, filtered and concentrated. The residue was purified with RP-HPLC (10-90% MeCN in H2O with 0.01% TFA as additive) to give 2-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-5-methyl-1,3,4-oxadiazole (33.6 mg, 11.1%). MS (ESI, pos. ion) m/z 335.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.89 (br. s., 1H), 9.20-9.29 (m, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.82 (dd, J=8.5, 1.7 Hz, 1H), 7.57-7.72 (m, 2H), 7.46 (d, J=7.4 Hz, 1H), 6.53 (d, J=8.0 Hz, 1H), 5.58 (dt, J=12.3, 6.2 Hz, 1H), 2.59 (s, 3H), 1.47 (d, J=6.1 Hz, 6H).
Reaction SMILES: CN(C(C1C=CC=CC=1)C1C=C([C:11]2[C:12]([NH:22][C:23](=[O:25])[CH3:24])=[C:13]([CH:18]=[CH:19][C:20]=2[Cl:21])[C:14](OC)=[O:15])C=CC=1)C.C(O)C.Cl>C1COCC1>[ClH:21].[OH:15][C:14]1[C:13]2[C:12](=[CH:11][CH:20]=[CH:19][CH:18]=2)[NH:22][C:23](=[O:25])[CH:24]=1
Reactant: COC(=O)c1ccc(Cl)c(-c2cccc(C(c3ccccc3)N(C)C)c2)c1NC(C)=O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1cc(O)c2ccccc2[nH]1

Procedure:
2.0 g (4.6 mmol) of methyl 3-(dimethylaminophenyl-methyl)phenyl-2-acetamido-4-chlorobenzoate are dissolved in 15 ml of THF. With cooling, 15 ml of a 1 molar solution of THF and KN[Si(CH3)3 ]2 are added dropwise with stirring. The mixture is additionally stirred at room temperature for 1 1/2 hours. The solvent is distilled off and the residue is treated with water. The solution thus obtained is washed with dichloromethane. The aqueous phase is adjusted to an acidic pH using hydrochloric acid and again extracted with dichloromethane. The organic phase separated off is dried. The solvent is distilled off. For further purification of the oil obtained, the product is taken up with ethanol, acidified with ethereal hydrochloric acid, triturated with ether and the product obtained is filtered off with suction. 7-Chloro-3-[dimethylamino-phenylmethyl)phenyl]-1,2-dihydro-4-hydroxyquinolin-2-one hydrochloride, dihydrate, m.p. ~230°, is obtained.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2N)=[CH:12][CH:11]=1.[ClH:21]>C(#N)C>[Cl:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[CH:19]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12]2
Reactant: Cl
Reactant: COc1ccc2cccc(N)c2c1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COc1ccc2cccc(Cl)c2c1
Temperature: 25 °C
Yield: 41 %

Procedure:
CuCl2 (4.6 g, 24.6 mmol) and t-butyl nitrite (4.46 g, 43.3 mmol), were added to acetonitrile (125 mL) at 0° C. To this mixture was slowly added a solution of 7-methoxynaphthylamine (4.99 g, 28.8 mmol) in acetonitrile (25 mL). The reaction was allowed to warm to room temperature, stirred with HCl (400 mL of 2N solution) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with 2N HCl, dried over sodium sulfate, filtered, evaporation of the solvent, and purification on a silica column (hexanes) yielded 2.27 g (41%) of an orange liquid. An analytical sample was further purified by reverse phase preparative HPLC to yield the title compound as a yellow solid: mp 32–34° C.;1H NMR (CDCl3): δ 3.98 (3H, s), 7.20 (1H, dd, J=2.52 Hz, J=8.96 Hz), 7.22–7.27 (1H, m), 7.52 (1H, d, J=2.47 Hz), 7.55 (1 h, d, J=7.47 Hz), 7.69 (1H, d, J=8.15 Hz), 7.75 (1H, d, J=8.95 Hz); MS m/z 191/193 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([OH:33])[CH:27]=2)=[CH:20][C:21]=1[CH3:22])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:23]([C:19]2[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[C:3]([OH:35])=[O:2])=[O:16])=[C:21]([CH3:22])[CH:20]=2)=[O:34])=[CH:27][C:28]=1[OH:33]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2ccc(F)c(O)c2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2ccc(F)c(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[5-(4-Fluoro-3-hydroxy-benzylcarbamoyl)-3-methyl-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acidmethyl ester (14 mg, 0.027 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (11 mg, 0.269 mmol) in water (2.5 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 12.3 mg (68%). MS m/e 506.2 (M+H+).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH2:30][C@@H:31]([OH:33])[CH3:32]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[CH:2][N:29]([CH2:30][CH:31]([OH:33])[CH3:32])[C:5]=3[C:6]=2[CH:7]=1
Reactant: C[C@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1CC(C)O)CC2
Reaction time: 0.5 h

Procedure:
A solution of 3 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-tetralone and 150 mg of p-toluenesulfonic acid in 130 ml in anhydrous toluene was heated on a water separator. A solution of 4.16 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 3.0 g (84%) of (S)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30]>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(-c2nnc(Cl)cc2-c2ccccc2)cc1
Product: COc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccccc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazine (215 mg, 0.725 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless needles (169.7 mg, 60.0%). Melting point: 169.0-169.9° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:22](O)[CH3:23]>>[C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:22][CH3:23])=[O:2]
Reactant: CCC(CCCCCC1=CCCC1=O)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(CC)CCCCCC1=CCCC1=O

Procedure:
Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 131) with thionyl chloride and then treatment of the acid chloride with ethanol in the manner described in Example 456 gives an amber oil. The oil is placed on a magnesia-silica gel column and eluted with 3:1 benzene:ether. The solvent is removed and the residue is distilled, b.p. 122° C. (0.06 mm).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].S(Cl)([Cl:19])(=O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Cl:19][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CCl)c1OC(F)F
Yield: 36.3 %

Procedure:
To a solution of 11.5 g (50.0 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 50 ml of carbon tetrachloride were added 10.1 g (75.0 mmol) of sulfuryl chloride and 0.8 (5.0 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 11 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.8 g (purity: 83.4%, yield: 30.3%) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=2)[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:29]=2)([C:14]2[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A mixture of methyl 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoate (865 mg, 1.34 mmol) in MeOH (10 mL)/THF (20 mL) and LiOH (2 N, 10 mL) was stirred at rt overnight. The reaction mixture was made acidic by addition of 1 N HCl to pH=1˜2 and concentrated. The resulting residue was partitioned between EtOAc and sat. NaCl. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO (40 g siligel column, 0-10% MeOH/DCM over 30 min) to yield 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoic acid as a colorless oil (650 mg, 81% yield). LCMS: RT=2.17 min [M+H] 600.88 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.45 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm).
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](C1C=CC=CC=1)(=O)[CH3:15].C(OCC)(=O)CCCC>>[C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10][CH2:11][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Agent: CCCCC(=O)OCC
Product: CCCCC(=O)CC(=O)c1ccccc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.2 g (18.3 mmol) of acetophenone and 4.51 g (35 mmol) of ethyl valerate to yield 2.6 grams of Intermediate 18:: TLC Rf=0.52 (1/9 EtOAc/Hexanes); 1H NMR (400 MHz, CDCl3) δ7.87 (m, 2H), 7.48 (m, 3H), 6.17 (s,1H), 2.42 (t, 2H, J=7.6), 1.67 (m, 2H), 1.4 (m, 2H), 0.95 (t, 3H, J=7.2); low resolution MS (ES+)m/e 205.1 (MH+), 227.1 (M+Na+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[CH:7][CH:6]=1.[OH-].[Li+].CO.Cl>O>[F:1][C:2]([F:14])([F:15])[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C([O-])c1ccc(C#CC(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C#CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a 100 mL round bottom flask was added 4-(3,3,3-trifluoroprop-1-ynyl)benzoate (0.68 g, 2.9 mmol), lithium hydroxide (0.71 g, 29 mmol), and methanol (30 mL): water (10 mL). The mixture was stirred at room temperature for 30 minutes, heated at reflux for 1 hour, and reduced in vacuo. Water (100 mL) was added and the mixture was cooled to 0° C. HCl (10 N) was added slowly to the stirred solution until the pH of the solution reached 5. A yellow precipitate formed and was filtered, washed with cold water (3×100 mL), and dried under vacuum to afford 0.540 g (86%) of 4-(3,3,3-trifluoroprop-1-ynyl)benzoic acid as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8](C(OCC(Cl)(Cl)Cl)=O)[C@H:9]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][N:5]([CH3:7])[CH:6]=1.OP([O-])(O)=O.[K+]>C1COCC1.[Zn]>[Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: COc1ccc(COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c2nn(C)cc2Br)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@H](CC(C)C)Nc2nn(C)cc2Br)cc1
Reaction time: 0.5 h

Procedure:
To 4-methoxybenzyl N-(4-bromo-1-methyl-1H-pyrazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (1.72 g, 2.89 mmol) in dry THF (50 mL) was added activated zinc powder (1.89 g, 28.9 mmol) followed by an aqueous solution of KH2PO4 (1.0 M, 5.8 mL, 11.6 mmol) and the reaction mixture was stirred for ½ hour. Additional aliquots of activated zinc powder (950 mg, 14.45 mmol) and aqueous solution of KH2PO4 (1.0 M, 2.9 mL, 2.9 mmol) were added and the reaction mixture stirred for 1½ hour. The zinc powder was filtered off, rinsed with Et2O and water and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 25/75, then 3/7) to afford 4-methoxybenzyl N-(4-bromo-1-methyl-1H-pyrazol-3-yl)leucinate.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[Cl:20][C:21]1[C:28]([Cl:29])=[C:27]([OH:30])[CH:26]=[CH:25][C:22]=1[CH:23]=O>>[Cl:20][C:21]1[C:28]([Cl:29])=[C:27]([OH:30])[CH:26]=[CH:25][C:22]=1[CH:23]=[CH:16][C:15]([C:13]1[S:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:19])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)-ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is crystallized from acetonitrile.
Reaction SMILES: BrCC1C=C[C:6]([C:7]([C:9]2[CH:28]=[CH:27][C:12]([CH2:13][N:14]3[C:22]4[C:21](=[O:23])[N:20]([CH3:24])[C:19](=[O:25])[N:18]([CH3:26])[C:17]=4[N:16]=[CH:15]3)=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.O>[CH3:24][N:20]1[C:21](=[O:23])[C:22]2[N:14]([CH2:13][C:12]3[CH:27]=[CH:28][C:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:40]([C:39]5[CH:38]=[CH:7][CH:6]=[CH:5][CH:4]=5)=[CH:41][C:42]=4[CH2:37][N:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)=[CH:10][CH:11]=3)[CH:15]=[N:16][C:17]=2[N:18]([CH3:26])[C:19]1=[O:25]
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(CBr)cc3)cc2)n(C)c1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(-c4ccccc4)cc3CN3CCNCC3)cc2)n(C)c1=O
Yield: 14.7 %

Procedure:
A solution of 7-[4-(4-bromomethylbenzoyl)benzyl]-1,3-dimethylxanthine (232 mg), potassium carbonate (109 mg) and 1-phenylpiperazine (92 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane: triethylamine =3:1:0.1) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (20 mg).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH4+:13].[OH-]>O>[NH2:13][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
4-Fluoro-3-nitrobenzaldehyde (3 g) was slowly added to 50 ml of conc. aq. NH4OH. After stirring for 3 h, the mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[S:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:29](Cl)Cl.CCN(C(C)C)C(C)C.FC(F)(F)S(OC)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])[S:11][CH3:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClCCl
Reactant: CC(C)[Si](OCc1snnc1C(=S)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: COS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=Nc1ccc(F)c(Cl)c1)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.08 h

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carbothioamide (0.18 g, 0.00039 mol) in anhydrous DCM (3 ml, 0.04 mol) under N2 was added DIPEA (82 μL, 0.00047 mol) followed by methyl trifluoromethanesulfonate (47 μL, 0.00043 mol). The reaction was stirred for 5 minutes and then concentrated in vacuo. The crude material was used in the next step. The product amount was estimated (185 mg, 100%). MF═C20H29ClFN3OS2Si; LCMS calculated for C20H30ClFN3OS2Si (M+H)+: m/z=474.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].N1(C(C2C=CC(Br)=CN=2)=O)CC[CH2:29]1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23]([N:24]3[CH2:25][CH2:29][CH2:26]3)=[O:27])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from azetidin-1-yl-(5-bromo-pyridin-2-yl)-methanone (167a) (1.37 g, 5.68 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.26 g, 5.58 mmol) to give a white foam (738 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=2.78 Hz, 1 H) 8.12 (d, J=8.59 Hz, 1 H) 7.31-7.38 (m, 1 H) 7.27 (s, 1 H) 7.21 (s, 1 H) 4.72 (t, J=7.71 Hz, 2 H) 4.27 (t, J=7.71 Hz, 2 H) 3.89 (s, 3 H) 2.92 (s, 2 H) 2.38 (t, J=7.71 Hz, 2 H) 1.50 (s, 6 H); LCMS for C21H22N2O5 m/z 383.20 (M+H+).
Reaction SMILES: [O:1]=[O+][O-].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]([OH:16])[CH2:13][CH:14]=C)[CH:5]=1>CO>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][OH:1])[CH:5]=1
Reactant: O=[O+][O-]
Reactant: C=CCC(O)CCc1cccnc1
Solvent: CO
Product: OCCC(O)CCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of ozone in air was passed through a solution of (±)-6-(3-pyridyl)-hex-1-en-4-ol (1.38 g) in methanol (70 ml) at 0° C. for 2 hours. The solution was flushed with nitrogen for 1 hour then sodium borohydride (2 g) was added portionwise. The mixture was stirred at room temperature for 20 hours and then concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with methanol:dichloromethane (1:19) and the required fractions concentrated under reduced pressure. Ethyl acetate (25 ml) and aqueous potassium tartrate solution (1 M, 25 ml) were added to the residue and the mixture stirred rapidly for 2 hours. The phases were separated and the aqueous phase extracted with ethyl acetate (10×25 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as an oil (1.20 g).
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.Br.[CH3:9][N:10]1[CH2:16][CH2:15][C:14]2=[CH:17][C:18](=[O:22])[C:19](=[O:21])[CH:20]=[C:13]2[CH2:12][CH2:11]1>CO>[OH:22][C:18]1[C:19]([OH:21])=[CH:20][C:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:16][CH2:15][C:14]=2[C:17]=1[S:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC2=CC(=O)C(=O)C=C2CC1
Reactant: SCc1ccco1
Agent: Br
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(SCc3ccco3)c2CC1

Procedure:
Following the procedures outlined in Example 17, 0.9 g. (0.0075 mole) of furfuryl mercaptan and 2 g. (0.0073 mole) of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrobromide were reacted in 200 ml. of methanol to yield 7,8-dihydroxy-6-furfurylthio-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, free base m.p. 162°-165° C.