Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[NH2:30][C:31]1[C:36]([CH:37]=O)=[C:35]([Cl:39])[N:34]=[CH:33][N:32]=1>C1COCC1>[Cl:39][C:35]1[N:34]=[CH:33][N:32]=[C:31]([NH2:30])[C:36]=1[CH:37]=[CH:2][O:3][CH3:4]
Reactant: Nc1ncnc(Cl)c1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1c(N)ncnc1Cl
Temperature: -2 °C
Reaction time: 1 h
Yield: 1.2 %

Procedure:
A suspension of (methoxymethyl)triphenylphosphonium chloride (276.0 g, 0.807 mol, 1.1 equiv) in THF (1.5 L) was cooled in an ice/salt bath to −2° C. and 1 M potassium tert-butoxide (KOtBu) in THF (807 mL, 0.807 mol, 1.1 equiv) was added over 1.5 h at −2 to −3° C. The deep red-orange mixture was stirred at −2 to −3° C. for 1 h. 4-Amino-6-chloropyrimidine-5-carbaldehyde (115.2 g, 0.7338 mol, 1.0 equiv) was then added portion wise to the reaction mixture as a solid form using THF (200 mL) to rinse the container and funnel. During the addition the reaction temperature increased from −3 to 13° C. and a brown color developed. When the reaction temperature dropped to 10° C., the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 42 h. The reaction mixture was cooled to −2° C. before being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble material at the interface, then extracted with 2 N HCl (4×250 mL) followed by 3 N HCl (2×250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice/brine bath, adjusted to pH 8 with a 6 N aqueous NaOH solution and extracted with EtOAc (3×1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, stirred with charcoal (10 g) and silica gel (10 g) for 1 h. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, co-evaporating residual EtOAc with n-heptane (500 mL). The resulting tan solid was pumped under high vacuum for 2 h to afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (72.3 g, 136.2 g theoretical, 53.1%). The crude desired product was used in the following reaction without further purification. A sample of crude product (2.3 g) was purified by silica gel column chromatography on, eluting with 0-35% EtOAc/n-heptane to give 1.7 g of pure 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine as a white solid, which was found to be a 1 to 2 mixture of E/Z isomers. 1H NMR (300 MHz, DMSO-d6) for E-isomer: δ 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J=13.1), 5.35 (d, 1H, J=13.0 Hz), 3.68 (s, 3H) ppm and for Z-isomer: δ 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J=6.8 Hz), 5.02 (d, 1H, J=6.7 Hz), 3.69 (s, 3H) ppm; C7H8ClN3O (MW, 185.61), LCMS (EI) m/e 186/188 (M++H).
Reaction SMILES: OO.[NH2:3][C:4]([CH3:22])([CH3:21])[CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.C([O-])([O-])=[O:24].[K+].[K+].CS(C)=O>O>[NH2:3][C:4]([CH3:22])([CH3:21])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:24])=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reaction time: 1 h
Yield: 169.7 %

Procedure:
Aqueous 30% H2O2 (62.1 mL, 548 mmol) was added dropwise to a mixture of 4-(4-(2-amino-2-methylpropyl)phenoxy)benzonitrile (53.2 g, 200 mmol), K2CO3 (15.78 g, 114 mmol) and DMSO (270 mL) over 20 min while the temperature was held at 20° C. with a cooling bath. The mixture was stirred at this temperature for 1 h after the addition was complete, and then water (209 mL) was added slowly. The slurry was cooled in an ice bath with stirring for 1 h, and the product was then filtered, washed with water and dried in vacuo at 50° C. to yield 55.0 g (97%) of white solid. Analysis by HPLC indicated purity of >99%. NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18]1.[NH4+].[Cl-]>C1COCC1.CCOCC>[F:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:17]1([OH:16])[CH2:20][CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18]1
Reactant: COc1ccc(Br)c(F)c1
Reactant: COC(=O)C1CC(=O)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(O)(c2ccc(OC)cc2F)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a dry and N2 flashed flask was added 4-bromo-3-fluoroanisole (1.04 g, 5.07 mmol) in THF (6 mL) under N2. This was cooled to −78° C., and n-BuLi (1.72 mL, 4.29 mmol) was added. The reaction was stirred at −78° C. for 30 min. The mixture above was added via cannula to a stirred solution of methyl 3-oxocyclobutane carboxylate (500 mg, 3.90 mmol) in dry Et2O (35 mL) at −78° C. under N2. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Satd aq. NH4Cl was added and the mixture was stirred until a clear solution resulted. This mixture was extracted with Et2O (3×). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product, which was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 260 mL, gradient to 40% EtOAc in hexanes over 5184 mL) to afford methyl 3-(2-fluoro-4-methoxyphenyl)-3-hydroxycyclobutanecarboxylate (450 mg, 45%). 1H NMR (500 MHz, CDCl3): δ 7.32 (t, J=8.9 Hz, 1H); 6.69-6.63 (m, 2H); 3.80 (s, 3H); 3.74 (s, 3H); 3.40 (s, 1H); 3.03-2.93 (m, 2H); 2.90-2.82 (m, 1H); 2.67-2.61 (m, 2H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[N:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[Cl:14][O-].[Na+]>O>[Cl:14][C:10]1[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]([OH:3])=[N:12][C:11]=1[CH3:13]
Reactant: [O-]Cl
Reactant: Cc1ccc(C(=O)O)c(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(O)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 15.7 g of 50% sodium hydroxide and 18.2 ml of water was added 10 g (0.065 mole) of 2-hydroxy-6-methylnicotinic acid. When the acid had dissolved, 200 ml of 5.25% aqueous sodium hypochlorite was added rapidly through a dropping funnel. The temperature was not moderated (slight exotherm did occur). The entire mixture was stirred at room temperature for 18 hr. The reaction mixture was then filtered and acidified with concentrated hydrochloric acid. The precipitate was recrystallized from isopropyl alcohol/ethereal to give ~6 g of analytically pure crystals, m.p. 291°-94° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-cyano-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 13; 200 mg, 0.75 mmol) in THF (2 ml) was added a solution of lithium hydroxide (94 mg, 2.25 mmol) in water (8 ml). The reaction mixture was stirred at room temperature overnight. The THF was removed and the mixture was adjusted to pH 7 with 2N HCl. The mixture was filtered and the residue dried to yield the title compound as a yellow solid. 160 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([C:5]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:24][CH2:25]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A suspension of 1.00 g (4.21 mmol) 5-bromo-2-chloro-3-nitro-pyridine, 0.993 g (4.63 mmol) of piperidin-4-ylmethyl-carbamic acid tert-butyl ester, and 1.16 g (8.42 mmol) of potassium carbonate in N,N-dimethylformamide (10 mL) is stirred for 2 hours under argon. The mixture is diluted with water which causes a solid to precipitate from solution. The formed solid is collected by filtration, washed with water, and dried for 1 hour under vacuum at 50° C. to give 1.57 g (90.0%) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([NH:22][CH3:23])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([N:22]([CH3:23])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: CNc1ccc(OC)cc1
Reactant: FC(F)(F)c1cc(Cl)c2ccccc2n1
Solvent: CC(=O)O
Product: COc1ccc(N(C)c2cc(C(F)(F)F)nc3ccccc23)cc1
Temperature: 105 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A mixture of 4-chloro-2-(trifluoromethyl)quinoline 0.232 g (1.0 mmol) and 4-methoxy-N-methylaniline 0.137 g (1.0 mmol) in glacial acetic acid 3 mL was stirred at 100-110° C. for 24 h. The reaction mixture was directly subjected to gradient column chromatography (EtOAc/hexanes, 0% to 50%) to give the titled compound in 70% yield. 1H NMR (CDCl3, 400 MHz): δ 8.11-8.08 (m, 1H), 7.62-7.58 (m, 1H), 7.58-7.55 (m, 1H), 7.27-7.22 (m, 2H), 6.97 (d, 2H, J=9.0 Hz), 6.84 (d, 2H, J=9.0 Hz), 3.79 (s, 3H), 3.49 (s, 3H). m/z: 333.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:5]=1[CH:6]=[CH:7][O:8][C:9]2=O)([O-:3])=[O:2].[NH3:15]>C(O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:5]=1[CH:6]=[CH:7][NH:15][C:9]2=[O:8])([O-:3])=[O:2]
Reactant: N
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CCO
Product: O=c1[nH]ccc2c([N+](=O)[O-])cccc12
Yield: 79.7 %

Procedure:
2.51 g (13.13 mmol) of 5-nitroisocoumarin is added into 100 ml of ethanol. Ammonia is pressure-forced in in an autoclave. The product precipitates and is suctioned off. 1.98 g (79.7%) of the desired compound is isolated.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1.Cl>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:24][CH:23]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Agent: Cl
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccc(Cl)cc1
Yield: 51 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 4-chloro-phenylhydrazine×HCl according to the method described for Example 1 in 51% yield.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][C@H:14]3[O:22]S(C)(=O)=O)[C:6]2=[N:5][C:4]=1[CH3:27])=[O:2].C([O-])(=O)C.[K+].O1CCOCCOCCOCCOCCOCC1.C(#N)C>ClCCl>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][C@@H:14]3[OH:22])[C:6]2=[N:5][C:4]=1[CH3:27])=[O:2]
Reactant: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3OS(C)(=O)=O)cccn2c1C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@@H]3O)cccn2c1C=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
1 g of 3-formyl-2-methyl-8-(2-(trans)-methylsulfonyloxy-2,3-dihydro-1-indenyloxy)-imidazo[1,2-a]pyridine is added to a mixture of 5.1 g of anhydrous potassium acetate, 13.8 g of 1,4,7,10,13,16-hexaoxacyclooctadecan ("18-crown-6) and 100 ml of anhydrous acetonitrile, while stirring and excluding any moisture. The brownish suspension is warmed for 18 hours at 70° C. and heated for a further 10 hours under reflux. After cooling, it is poured onto water and extraction carried out several times with dichloromethane. The organic phases are washed with water, dried and the solvent stripped off in vacuo. The dark brown residue is assayed by chromotography with the mobile phase ethyl acetate/methanol=95:5 (V/V) over silica gel. After stripping off of the solvent, the residue (0.18 g) is dissolved in 3.6 ml methanol and this solution is added dropwise with stirring to a solution of 0.072 g potassium hydroxide in 1.2 ml water. Stirring continues for one hour at room temperature, water is added, the pH is adjusted with diluted acetic acid to 6 and extraction is carried out several times with dichloromethane. The organic phases are washed with water, dried and the solvent is stripped off in vacuo. 115 mg of the title compound as a yellowish residue of m.p. 171°-173° C. is obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10](F)=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH:2]=[CH2:3].[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:39][N:40](C)C=O>O>[CH2:1]([O:4][C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:39]#[N:40])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: CN(C)C=O
Reactant: C=CCOc1cn(C)c2cc(F)ccc2c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: C=CCOc1cn(C)c2cc(C#N)ccc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-allyloxy-7-fluoro-1-methyl-4quinolone, obtained as described in Example 8a, (2.3 g), potassium cyanide (1.0 g), 18-crown-6 ether (5.0 g) and dimethylformamide (200 ml) was stirred at 95° for 2 days. After cooling to ambient temperature, the mixture was poured into water (600 ml) and extracted with dichloromethane (3×150 ml). The combined extracts were washed with water (2×200 ml), dried over magnesium sulphate and the solvent was removed by distillation. The residue was triturated with diethyl ether (50 ml) and the resultant solid added to a mixture of potassium cyanide (1.0 g), 18-crown-6 ether (5.0 g) and dimethylformamide (200 ml). The resultant solution was stirred at 140° for 16 hours and then allowed to cool to 60°. The solvent was removed under reduced pressure at 60° and the residue was partitioned between water (100 ml) and dichloromethane ( 200 ml). The dichloromethane solution was dried over magnesium sulphate and filtered through silica gel (30 g). The filter bed was washed with dichloromethane (5×100 ml) and the combined filtrate and washings were evaporated to give crude 3-allyloxy-7-cyano 1-methyl-4-quinolone.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].B(Br)(Br)Br>C(Cl)Cl.CC(C)=O>[OH:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1]
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Agent: BrB(Br)Br
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In round bottom flask, melatonin (48 mg, 0.21 mmol) was taken in dry CH2Cl2 (3 ml). The reaction mixture was cooled to −78° C. by keeping in acetone bath with liquid nitrogen. To this chilled reaction mixture boron tribromide (0.12 ml, 12 mmol) was added dropwise and stirring continued at this temperature for another 1 h. Then the reaction mixture was stirred overnight at room temperature for overnight. Completion of reaction was monitored by TLC; the reaction mixture was quenched by addition of water, and 10% Hcl and extracted with ethyl acetate. The combined organic phases were washed with water (20 mL) and brine (10 mL) and dried over sodium sulfate. The organic layer was removed under reduced pressure. The crude product was purified by silica gel column chromatography to give N-(2-(5-hydroxy-1H-indol-3-yl)ethyl) acetamide (5a). Isolated as reddish colored semi solid (20 mg, 45%), by elution with 6% methanol in chloroform.
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1.O=S(Cl)[Cl:15]>CCOCC>[Cl:15][CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c(CO)csc12
Solvent: CCOCC
Product: Cc1cccc2c(CCl)csc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
290 mg of 3-hydroxymethyl-7-methyl-benzo[b]thiophene are dissolved in ether, 0.6 ml SOCl2 added and the mixture stirred for 2 hours at room temperature. The reaction mixture is poured onto ice and the organic phase washed neutral, dried and concentrated under vacuum. The crude 3-chloromethyl-7-methyl-benzothiophene thus obtained is dissolved in acetone, mixed with an aqueoug solution of 170 mg of KCN and refluxed for 18 hours. The reaction mixture is concentrated, the residue partitioned between water and ether and the organic phase washed, dried, concentrated and chromatographed over silica-gel (eluant: toluene) to yield the title product is an oil.
Reaction SMILES: C1(=O)OC(=[O:5])C=C1.OO.[Br:10][CH2:11][C:12]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]>C(O)(=O)C>[Br:10][CH2:11][C:12]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[O:5]1
Reactant: O=C1C=CC(=O)O1
Reactant: Fc1ccc(C(=Cc2ccccc2Cl)CBr)c(F)c1
Agent: OO
Solvent: CC(=O)O
Product: Fc1ccc(C2(CBr)OC2c2ccccc2Cl)c(F)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
Maleic anhydride (2.05 g, 20.9 mmol) and then hydrogen peroxide (35% by weight strength solution, 2.04 g, 20.9 mmol) were added to a stirred solution of 1-[3-bromo-1-(2-chlorophenyl)prop-1-en-2-yl]-2,4-difluorobenzene (720 mg, 2.09 mmol) in acetic acid (20 ml). The reaction mixture was stirred at 40° C. for 24 h, more hydrogen peroxide (35% by weight strength solution, 2.04 g, 20.9 mmol) was then added and the reaction mixture was stirred at 20° C. for 66 h. Excess oxidizing agent was quenched by addition of sat. aq. sodium thiosulphate. The mixture was extracted with dichloromethane, and the organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification of the residue on silica gel gave 2-(bromomethyl)-3-(2-chlorophenyl)-2-(2,4-difluorophenyl)oxirane as a 59/41 mixture of diastereoisomers [316 mg, colourless oil, yield 40%; GC/MS: m/z=279 ([M-Br]+); HPLC/MS: log P(HCOOH)=4.61 (major diastereoisomer), 5.00 (minor diastereoisomer)].
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O:38][C:39](=[O:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47](O)[CH3:48])=[CH:43][CH:42]=1)C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C@H:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][C:39]([OH:50])=[O:38])=[CH:42][CH:43]=1)[CH3:48])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(C(C)O)cc1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: Oc1ccccc1
Product: C[C@H](Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccc(CC(=O)O)cc1

Procedure:
The title compound was prepared using the procedure of example 69 using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol as the phenol and [4-(1-Hydroxy-ethyl)-phenyl]-acetic acid ethyl ester as the alcohol .MS (ESI) m/z 540;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].[F:28][C:29]1[CH:36]=[CH:35][C:32](C=O)=[CH:31][CH:30]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:12][N:13]([CH2:15][C:32]3[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=3)[CH2:14]1)[CH2:10][C:9]2=[O:26]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccc(F)cc3)C1)O2

Procedure:
(E)-3-[1′-(4-Fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester was synthesized starting from Intermediate 4 (350 mg, 1.13 mmol), according to the procedure described in Example 31, Step A, using 4-fluorobenzaldehyde (0.24 ml, 2.26 mmol) and NaBH(OAc)3 (360 mg, 1.69 mmol). The product was obtained as a yellow solid (390 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18]C(=O)OC(C)(C)C)=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[C:9]=2[CH3:28])=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[C:9]=2[CH3:28])=[CH:4][CH:3]=1
Reactant: CC1=C(c2ccc(F)cc2)c2ccc(NC(=O)OC(C)(C)C)cc2OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1=C(c2ccc(F)cc2)c2ccc(N)cc2OC1(C)C

Procedure:
The compound obtained in (4) described above (126 mg) and 4N hydrochloric acid-dioxane solution (3 mL) were treated in the same manner as Reference Example 5(5) to give the titled compound (66 mg) as a pale brown viscous oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:21][CH:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23]>>[CH3:21][CH:22]([S:24]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:5]=[CH:6][C:7]([S:10][CH3:11])=[CH:8][CH:9]=1)(=[O:26])=[O:25])[CH3:23]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CSc1ccc(C(C#N)=NO)cc1
Solvent: CCN(CC)CC
Product: CSc1ccc(C(C#N)=NOS(=O)(=O)C(C)C)cc1
Yield: 67.6 %

Procedure:
Analogously to the preparation of Example 3.4, 9.6 g (0.5 mol) of α-hydroxyimino-4-methylthiobenzyl cyanide are reacted, in the presence of 7.6 g (0.075 mol) of triethylamine, with 7.85 g (0.055 mol) of 2-propanesulfonyl chloride. After working-up, the crude product is recrystallised from acetic acid acetate/hexane. 11.1 g (83%) of α-(2-propylsulfonyloxyimino)-4-methylthiobenzyl cyanide are obtained in the form of beige crystals having a melting point of 83-87° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 350 nm (ε=14660) that extends to 435 nm. Elemental analysis: C12H14N2O3S2 (266.32)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br)#[N:26].C1CCCCC1>C(OCC)(=O)C>[C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][O:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1)#[N:26]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@]12CCNC2=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3C#N)cc2)CC[C@]12CCNC2=O
Yield: 90.4 %

Procedure:
The title compound (102 mg, 90%) was prepared using a similar procedure as set out earlier in Description 11 starting from 1,1-dimethylethyl (2R,5R)-2-(4-hydroxyphenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D25, 84 mg, 0.252 mmol) and 2-cyanobenzyl bromide (74 mg, 1.5 eq); Rt (HPLC): 5.37 min; Rf (cyclohexane:ethyl acetate=1:1): 0.07; MS: (ES/+) m/z: 470 [M+Na+]. C26H29N3O4 requires 447.