Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:5])C.[NH:15]([C:17]1[N:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[NH2:16].O>ClCCl.CO>[CH3:5][C:4]1[N:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]([C:17]2[N:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[N:16]=1
Reactant: CCOC(C)=NC(=O)c1ccccc1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 51 %

Procedure:
N-(1-ethoxy-ethylidene)-benzamide 400 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-(3-methyl-5-phenyl-[1,2,4]triazole-1-yl)-pyridine-3-sulfonic acid amide (336 mg, yield: 51%) was obtained as a solid phase.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)(O)[O-].[Na+].[C:22](Cl)(Cl)=[S:23]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([N:16]=[C:22]=[S:23])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: S=C(Cl)Cl
Reactant: Cc1cnc(N)c(-c2ccc(F)c(F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cnc(N=C=S)c(-c2ccc(F)c(F)c2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(3,4-difluorophenyl)-5-methylpyridin-2-amine (0.6 g, 2.7 mmol) in dichloromethane (15 mL) was added a solution of sodium bicarbonate (2.3 g, 26.7 mmol) in water (25 mL) followed by a solution of thiophosgene (0.25 mL, 3.2 mmol) in dichloromethane (1 mL) and the mixture stirred for 15 minutes. The phases were separated and the organic phase was dried with sodium sulfate and the solvent was evaporated in vacuo to afford the title compound was obtained as a crystalline yellow solid (0.7 g, 100%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8](N)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[Na+].Cl.[CH3:20]O>>[CH3:20][O:9][C:8](=[O:17])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: [OH-]
Reactant: CO
Reactant: NC(=O)C(c1ccccc1)c1ccccn1
Agent: Cl
Agent: [Na+]
Product: COC(=O)C(c1ccccc1)c1ccccn1
Temperature: 0 °C
Yield: 59 %

Procedure:
(RS)-Phenyl-pyridin-2-yl-acetamide (0.340 g, 1.60 mmol) was dissolved in 5 ml of a saturated solution of HCl/methanol and refluxed for 6 h in a closed vessel. The mixture is poured on 25 g of ice, the pH is adjusted to 8-9 by cautious addition of 28% sodium hydroxide solution keeping the temperature below 10° C. and the product is extracted with ethyl acetate/water. After drying (MgSO4) and concentration, the crude material is purified by flash chromatography on silicagel using 1:4 mixture of ethyl acetate and hexane as eluant to yield 0.204 g (0.939 mmol, 59%) of (RS)-phenyl-pyridin-2-yl-acetic acid methyl ester as a white solid, m.p. 74° C. and MS: m/e=228.2 (M+H+).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=12)=O.Cl.[CH:29]1([NH:34][C:35]([NH2:37])=[NH:36])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN1CCCC1=O.O>[CH:29]1([NH:34][C:35]2[N:37]=[C:5]([C:7]3[C:8]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:9][N:10]4[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:11]=34)[CH:4]=[CH:3][N:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: N=C(N)NC1CCCC1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(-c2nn3cc(C(F)(F)F)ccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 140 °C
Yield: 55.7 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one (314 mg, 0.83 mmol)) in 1-methyl-2-pyrrolidinone (3 mL) was added N-cyclopentylguanidine hydrochloride (271 mg, 1.66 mmol) and potassium carbonate (229 mg, 1.66 mmol). The mixture was heated at 140° C. for 8 hours. Upon cooling to room temperature, ether was added followed by water. The organics were washed with brine, and the aqueous layer was extracted with ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (4:1 hexanes-ethyl acetate) to give N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (204 mg, 56%) as a white solid. 1 H NMR (CDCl3): δ 8.84 (s, 1 H), 8.51 (d, 1 H), 8.11 (d, 1 H), 7.64 (dd, 2 H), 7.44 (dd, 1 H), 7.17 (t, 2 H), 6.33 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15–2.06 (m, 2 H), 1.84–1.52 (m, 6 H); 19F NMR (CDCl3): δ −62.70, −112.25; MS m/z 442 (M+1); mp 155–156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[N:7][S@](C(C)(C)C)=O)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH3:20][Mg]Br>ClCCl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C@H:6]([NH2:7])[CH3:20])=[C:4]([C:16]([F:17])([F:18])[F:19])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)N=Cc1ccc(Cl)cc1C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)c1ccc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
To a stirred solution of the crude (S)—N-(4-chloro-2-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (26.8 g, 86.0 mmol) in dichloromethane (290 mL) at −48° C. was added a solution of methyl magnesium bromide (3.0 M in diethyl ether, 63.0 mL, 189.0 mmol) dropwise. The reaction was stirred below −40° C. for 18 h, and the reaction was slowly warmed to 0° C. and quenched with 50% saturated aqueous ammonium chloride solution (100 mL). The phases were separated, and the organic layer was washed with deionized water (50 mL). The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to afford the desired product (14.6 g, 44.5 mmol, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:10].CN1CCOCC1.Cl[C:33]([O:35][CH3:36])=[O:34].O>CC1CCCO1>[CH3:36][O:35][C:33]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:10])=[O:34]
Reactant: Nc1ccccc1CC(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Solvent: O
Product: COC(=O)Nc1ccccc1CC(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: -12 °C
Reaction time: 1 h

Procedure:
50 ml of 2-methyltetrahydrofuran are distilled off from the solution consisting of 9.15 g (28.29 mmol, 1.0 eq) 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-phenylacetamide in 162 ml of 2-methyltetrahydrofuran. The solution is cooled to −12° C. and 4.56 g (45.10 mmol, 1.6 eq) 4-methylmorpholine are added, followed by 4.26 g (45.10 mmol, 1.6 eq) methyl chloroformate. The reaction mixture is stirred for another 1 hour at 20° C. and then combined with 100 ml of water. After phase separation the aqueous phase is washed with 20 ml 2-methyltetrahydrofuran and the combined organic phases are washed with 50 ml of water. The organic solvent is distilled off in vacuo. The residue is combined with 50 ml of acetone and refluxed. Then 100 ml of water are added and the suspension obtained is cooled to 20° C. To complete the crystallisation the mixture is stirred for 30 minutes at 20° C. Then the product is suction filtered, washed with 30 ml acetone-water mixture (1:2) and dried in the dryer at 45° C. while being rendered inert.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To the solution of p-acetylphenol (10 g) in DMF (50 ml) were added potassium carbonate (12.2 g) and t-butyl bromoacetate (16.2 ml), and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After the solvents were removed by distillation, crystals thus obtained were washed with n-hexane to give 17.7 g of t-butyl 4-acetylphenoxyacetate (yield, 96%).
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].Cl[C:17]1[N:22]=[C:21]([C:23]#[N:24])[C:20]([S:25][CH2:26][CH3:27])=[CH:19][CH:18]=1.C>C(Cl)Cl.CS(C)=O.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:15][C:17]1[N:22]=[C:21]([C:23]#[N:24])[C:20]([S:25][CH2:26][CH3:27])=[CH:19][CH:18]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCSc1ccc(Cl)nc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(Oc2ccc(Cl)c(Cl)c2)nc1C#N
Temperature: 0 °C
Yield: 77.8 %

Procedure:
In a reaction flask were placed 110 ml of THF, 10 ml of DMSO and 5.6 g of t-BuOK. 3,4-Dichlorophenol (8.2 g) was added and the mixture was stirred until solution was achieved. To this was added 9.9 g of 6-chloro-3-ethylthio-2-pyridinecarbonitrile and the reaction mixture was heated at reflux temperature for about 5 hours. After cooling, the contents of the flask were poured onto 500 g of ice, stirred until the ice had melted and then filtered. The solid obtained by filtration was dissolved in CH2Cl2, treated with charcoal, dried and was concentrated. Upon dilution with hexane, 12.6 g (77.5%) of 6-(3,4-dichlorophenoxy)-3-ethylthio-2-pyridinecarbonitrile was obtained as a tan crystalline material, m.p. 64°-66° C. Subsequent analysis by differential scanning calorimetry indicated that the compound obtained was polymorphic and existed in two crystalline forms: one melting at 66°-69° C., and the other at 81°-87° C.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1>CCCCCC.C(OCC)(=O)C>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Reactant: Brc1cccs1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccs1)OCC2c1ccc(C(C)C)cc1
Yield: 58 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromothiophene, the title compound was synthesized in the same manner as in Example 107. Yield: 58%. Melting point: 155-156° C. (hexane-ethyl acetate).
Reaction SMILES: [NH:1]([CH2:8][C:9]1([CH3:35])[CH:13]([C:14]([O:16]CC(Cl)(Cl)Cl)=[O:15])[N:12]2[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:11]2[S:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CN(C)C=O.[Zn]>[NH:1]([CH2:8][C:9]1([CH3:35])[CH:13]([C:14]([OH:16])=[O:15])[N:12]2[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:11]2[S:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reaction time: 6 h
Yield: 65.4 %

Procedure:
2,2,2-Trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.00 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.5 ml) and then zinc powder under cooling at -15° C. and the mixture was stirred for 6 hours. After the reaction, zinc powder was filtered off and the filtrate was poured into ethyl acetate. The solution was washed 4 times with water and dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was dissolved in a small amount of methanol and then pulverized by adding water to the solution. The powder was collected by filtration, washed with water and dried to give 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylic acid (0.50 g), mp. 120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:27][C:22]1[CH:21]=[C:20]([CH:10]([NH:11][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: Cc1ccc(C(N[C@@H](C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(N[C@@H](C)c2ccccc2)c2cccc(N)c2)cc1C
Yield: 77.8 %

Procedure:
In a similar manner to that described in Example (1b), a solution of isomer B of N-[(3-nitrophenyl)-(3,4-dimethylphenyl)methyl]-N-[(S)-1-phenylethyl]amine (1.19 g) in methanol (20 ml), nickel chloride hexahydrate (1.57 g) and sodium borohydride (500 mg) were reacted, to afford isomer B of the title compound (849 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10]>S(=O)(=O)(O)O>[C:9]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(F)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.5 %

Procedure:
Concentrated sulfuric acid (30 mL) was added to 4-fluorophenol (50 g, 446 mmol) and tert-butanol (60 g, 810 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was partitioned between hexane and water, and the hexane layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane) to give the title compound (6.8 g, 7%) as a colorless oil.
Reaction SMILES: CN([CH:4]([N:8]([CH3:10])[CH3:9])N(C)C)C.[CH3:11][O:12][P:13]([NH:17][CH:18]1[C:25](=[O:26])[N:24]2[CH:19]1[S:20][CH2:21][C:22]([CH3:40])=[C:23]2[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])([O:15][CH3:16])=[O:14]>>[CH3:11][O:12][P:13]([NH:17][CH:18]1[C:25](=[O:26])[N:24]2[CH:19]1[S:20][CH2:21][C:22]([CH:40]=[CH:4][N:8]([CH3:9])[CH3:10])=[C:23]2[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([O:15][CH3:16])=[O:14]
Reactant: COP(=O)(NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C)CSC12)OC
Reactant: CN(C)C(N(C)C)N(C)C
Product: COP(=O)(NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(C=CN(C)C)CSC12)OC

Procedure:
By following the procedure of Example 3, but replacing the bis-dimethylamino-t-butoxymethane by trisdimethylaminomethane (1.75 cc) and starting from 7-dimethoxyphosphorylamino-3-methyl-2-(4-nitrobenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.3 g), 7-dimethoxyphosphorylamino-3-(2-dimethylaminovinyl)-2-(4-nitrobenzyloxycarbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E isomer) (1.5 g) is obtained in the form of an orange crystalline powder, m.p.=236°-237° C. An analytically pure sample is obtained by recrystallisation from acetonitrile: yellow crystals, m.p.=252°-253° C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.[CH2:24](O)[CH3:25]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:14]([O:16][CH2:24][CH3:25])=[O:15])=[CH:9][CH:8]=1
Reactant: O=C(O)C(=Cc1ccncc1)c1ccc(F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=Cc1ccncc1)c1ccc(F)cc1

Procedure:
Conc. sulfuric acid (2.2 ml) was added carefully to a suspension of 2-(4-fluorophenyl)-3-(4-pyridyl)-acrylic acid (6.7 g, 27.5 mmol) in ethanol (120 ml) and the mixture was heated at reflux for 24 h. The solvent was evaporated, the remainder was taken up in dichloromethane and the organic solution was washed with aqueous sodium hydrogencarbonate and water, followed by drying and evaporation. Flash column chromatography on silica gel (hexane-acetone=2:1) provided the pure title compound. MS (m/z): 271.8 (M+H)+; C16H14FNO2requir. 271.3 1H-NMR (CDCl3): 8.44, 6.88 (2m, each 2H, Pyrid.), 7.72 (s, 1H, CH═), 7.16, 7.06 (2m, each 2H, PhF), 4.28 (q, 2H, CH2), 1.28 (t; 3H, CH3).
Reaction SMILES: I[C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH3:30][Sn](C)(C)C.O>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: C[Sn](C)(C)C
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2ccccc2c(-c2ccc(OS(C)(=O)=O)cc2)c2c1sc1ccccc12
Temperature: 103 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A suspension of methanesulfonic acid 4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (1.65 g, 3.11 mmole), tetramethyltin (3.58, 25.8 mmole), and bis(triphenylphosphine)palladium II chloride (0.218 g, 0.311 mmole 10 mole %) in dry N,N dimethylformamide (16 mL) was heated in a sealed vessel under argon at 103° C. for 4 hours and left at room temperature overnight. The reaction mixture was added to water (200 mL) and extracted with ether. Silica gel (40 mL) was added and the solvent removed. The adsorbate was flash chromatographed (85:15 Petroleum ether:ethyl acetate) to give the title compound as a pale yellow solid (1.12 g, 86%): mp 172-173° C.; NMR (CDCl3); δ 8.18 (ddd, J=8, 1, 1 Hz, 1H), 7.81 (ddd, J=1, 1, 8 Hz, 1H), 7.62-7.55 (m, 3H), 7.50-7.48 (m, 2H), 7.44-7.34 (m, 2H), 7.06 (ddd, J=8, 7, 1 Hz, 1H), 6.64 (ddd, J=8, 1, 1 Hz), 3.32 (s, 3H), 2.99 (s, 3H); MS: EI [m/z] 418 (100%); Anal. Calcd. for C24H18O3S2: C, 68.87, H, 4.34, N, 0.00. Found: C, 68.60, H, 4.26, N, 0.02.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[O:23][CH3:24])([O-:3])=[O:2].[H-].[Na+].[C:27](OC(=O)C)(=[O:29])[CH3:28].Cl>CN(C)C=O>[C:27]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:8]1)(=[O:29])[CH3:28]
Reactant: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc([N+](=O)[O-])cc12
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
A solution of 4-(5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid (0.6 g.) in N,N-dimethylformamide (DMF), (3 ml.) was added to a stirred suspension of oil-free sodium hydride (0.088 g.) in DMF (8 ml.) under a nitrogen atmosphere at ambient temperature. The red solution was stirred for 20 minutes, and acetic anhydride (0.187 g.) added. After 1 hour, the mixture was poured into hydrochloric acid (1N, 30 ml.), extracted with ethyl acetate (3×50 ml), the combined extracts washed with water (2×20 ml.), brine, dried (MgSO4) and evaporated. The product was crystallized from a mixture of tetrahydrofuran and ether to give 4-(1-acetyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid (0.455 g., 67%) as a yellow powder; partial NMR (250 MHz, DMSO-d6): 2.68(s,3H, NCOCH3); 3.95(s,3H, OMe); 4.13(s,2H, ArCHhd 3).
Reaction SMILES: C(O)=O.C(N(CC)CC)C.CC1(C)[O:19][C:17](=[O:18])[CH2:16][C:14](=O)O1.C(=O)[C:22]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[C:24]([O:25][CH3:26])[CH:23]=1>C(#N)C>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH2:14][CH2:16][C:17]([OH:19])=[O:18])[CH:31]=[CH:30][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 82 °C
Yield: 68.5 %

Procedure:
After adding 2.1 ml of the mixture of formic acid and triethylamine prepared as described in Example 1 to 20 ml of acetonitrile, 3.60 g (0.025 mol) of Meldrum's acid and 4.15 g (0.025 mol) of veratraldehyde were added to the reaction mixture. After heating same to its boiling point (82° C.) within 30 minutes and refluxing it for 4 hours, the acetonitrile was evaporated under reduced pressure, then the method of Example 1 was followed to give 3.6 g of a product, m.p.: 91°-93.5° C., which was recrystallized from aqueous methanol of 50% by volume.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[N:17][OH:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH2:19]([O:21][C:22](OCC)([CH3:24])[CH3:23])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH2:19]([O:21][C:22]([O:18][N:17]=[C:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)([CH3:24])[CH3:23])[CH3:20]
Reactant: ON=C(Cc1cccnc1)c1c(F)cccc1F
Reactant: CCOC(C)(C)OCC
Solvent: Cc1ccccc1C
Product: CCOC(C)(C)ON=C(Cc1cccnc1)c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 7.45 g of 2',6'-difluoro-2-(3-pyridyl)acetophenone oxime in 170 ml of xylene is mixed with 8.00 g of diethoxypropane and then heated to 80° C. with stirring. After a clear solution has formed, 0.20 g of pulverised Amberlyst® A15 is added and the entire mixture is heated to reflux temperature. After 6 hours, the reaction mixture is subjected to clarifying filtration through Celite® and the filtrate is freed of excess solvent at 60° C. in a water jet vacuum. After drying in a high vacuum, 2',6'-difluoro-2-(3-pyridyl)acetophenone O-(1-ethoxy-1-methylethyl)oxime is obtained as an E/Z isomer mixture in the form of a yellow oil. On chromatographic separation on silica gel using n-hexane/ethyl acetate (3:1), the E isomer [1H-NMR (CDCl3, 200 MHz): 1.428 ppm (s, --C(CH3)2)] is obtained first in the form of slightly yellowish oils.