Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([O:17][CH3:18])([C:15]#[N:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH3:20].C(O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH:15]([NH2:16])[CH2:19][CH3:20])([O:17][CH3:18])[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(C#N)CCC(OCc2ccccc2)CC1
Reactant: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(N)C1(OC)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon, 1.2 g of 39 were dissolved in 60 mL of absolute toluene. Then, 2.9 mL of ethylmagnesium bromide (3M in diethylether) were added dropwise. The mixture was allowed to warm to room temperature. After conversion was complete, the reaction mixture was cooled to 5° C. and 2 mL of dry ethanol were added. The mixture was filtered over celite and the filter cake was washed with tetrahydrofuran. Volatiles were removed in vacuo, the residue was dissolved in 20 mL of dry ethanol, 331 mg of sodium borohydride were added and the mixture was stirred for 2 h at 0° C. The mixture was evaporated, 20 mL of methyl tert.butyl ether and 20 mL of water were added and 1N aqueous hydrochloric acid was added dropwise until gas evolution ceased. The organic layer was separated, washed with brine, dried and evaporated to give 1 g of the desired product as a cis/trans mixture. Rt=0.96/0.99 min (Method M). Detected mass: 278.3 (M+H+).
Reaction SMILES: C(O[C:9](=O)[N:10]([CH2:12][C:13](=[O:35])[NH:14][CH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)C)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[C:29]1([S:26]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[C:16]([CH2:15][NH:14][C:13](=[O:35])[CH2:12][NH:10][CH3:9])=[CH:17][CH:18]=[CH:19]3)(=[O:28])=[O:27])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(CC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CNCC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
To a stirring solution of {[(6-Benzenesulfonyl-naphthalen-1-ylmethyl)-carbamoyl]-methyl}-methyl-carbamic acid benzyl ester in methanol and formic acid at room temperature is added palladium on carbon. The mixture is stirred at room temperature, filtered thru Celite, and the filtrate is concentrated to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-2-methylamino-acetamide.
Reaction SMILES: B(Br)(Br)[Br:2].I[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:24]>ClCCl>[Br:2][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:24]
Reactant: BrB(Br)Br
Reactant: COc1ccc(-c2cc(=O)c3cc(I)ccc3o2)cc1
Solvent: ClCCl
Product: O=c1cc(-c2ccc(O)cc2)oc2ccc(Br)cc12
Reaction time: 30 h

Procedure:
A dichloromethane solution (4.9 ml) that contained boron tribromide was slowly added to a dichloromethane solution (85 ml) that contained compound 19 (185 mg, 0.489 mmol) while stirring under cooling on ice, and the reaction was then carried out for 30 hours. After completion of the reaction, purified water (80 ml) was added to the reaction solution, and the dichloromethane layer was extracted. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate/hexane (1/4) as an elution solvent, so as to obtain a product of interest, 6-bromo-4′-hydroxyflavone (compound 20). Yield: 79 mg (yield constant: 44.3%) 1H NMR (300 MHz, DMSO6) 610.37 (s, 1H), 8.27 (s, 1H), 8.28-8.30 (m, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.7 Hz, 1H), 6.93-6.95 (m, 3H). MS m/z 364 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:11][C:10]([CH:21]=O)=[N:9]1.[CH3:23][NH2:24].CO.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:11][C:10]([CH2:21][NH:24][CH3:23])=[N:9]1
Reactant: Cc1ccc(Sc2cc(C=O)nn2-c2ccccc2Cl)nc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(Sc2ccc(C)cn2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(5-methylpyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (422 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.3 mL) and methanol (4 mL) at 0° C. The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), sodium borohydride (60 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 433 mg, 98%).
Reaction SMILES: [CH3:1]C1C=CC(OC2C=CC(N)=CC=2)=CC=1.[CH2:16]([N:20]([CH2:34][CH:35]1[O:37][CH2:36]1)[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[CH:17]1[O:19][CH2:18]1>>[CH2:34]([N:20]([CH2:16][CH:17]1[O:19][CH2:18]1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:1])=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[CH:35]1[O:37][CH2:36]1
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1
Reactant: c1ccc(Oc2ccc(N(CC3CO3)CC3CO3)cc2)cc1
Product: Cc1ccc(Oc2ccc(N(CC3CO3)CC3CO3)cc2)cc1

Procedure:
Except that 4-(4-methyl phenoxy)aniline was used as the amine compound acting as precursor for synthesizing the epoxy resin, the same procedures as for the N,N-diglycidyl-4-phenoxy aniline was carried out under the same reaction conditions for glycidyl formation, producing N,N-diglycidyl-4-(4-methyl phenoxy)aniline
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].O>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:14])[CH:15]=[CH:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cn1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C=Cc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 6-methoxy-pyridine-3-carbaldehyde (1 g, 7.29 mmol, 1 eq) in 50 ml of dry DCM was added portionwise (methoxycarbonylmethylene)triphenylphosphorane (1.05 eq, 2.56 g). The mixture was stirred at room temperature for 16 hours (overnight). The mixture was then poured into 200 ml of water and the organic substances were extracted with DCM (twice, 150 ml of DCM was used in total) The gathered DCM layers were dried and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 100 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 3-22% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 3-(6-methoxy-pyridin-3-yl)-acrylic acid methyl ester (1.04 g, yield=73.8%, purity=95%). MS: [M+H]+=194.17 1H NMR (300 MHz; CDCl3) δ/ppm 3.81 (s, 3H), 3.97 (s, 3H), 6.34 (d, J=16.02 Hz, 1H), 6.77 (d, J=8.79 Hz, 1H), 7.65 (d, J=16.02 Hz, 1H), 7.77 (dd, J=8.70 Hz, J=2.40 Hz, 1H), 8.27 (d, J=2.40 Hz, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O.O.O1CCCC1>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[N:10]=3)[CH:7]=2)=[N:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.5 %

Procedure:
To a solution of N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.921 mmol) and 2-chloro-5-nitropyridine (175 mg, 1.1 mmol) in dimethyl sulfoxide (3 mL) was added cesium carbonate (450 mg, 1.38 mmol), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate, tetrahydrofuran and water were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (111 mg, 36%) as a brown solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[O:1]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCOc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)CCOc1ccccc1
Yield: 2255.8 %

Procedure:
A solution of 3-phenoxypropionic acid (25 g, 150.4 mmol) and p-toluenesulfonic acid (1.23 g, 6.46 mmol) in 500 mL of methanol was heated to reflux under nitrogen atmosphere in a 1 L round-bottom flask though 3 Å, 8-12 mesh molecular sieves which is equipped with a soxhlet extractor and condenser. The mixture was heated at reflux for 21 hr and then cooled. Methanol was removed on a rotary evaporator to leave a light yellow oil which was taken up in 50 mL of water and then extracted with ether (3×75 mL). The combined ether extracts were washed with NaHCO3 solution, water and brine and dried over MgSO4. Removal of the solvent and then Kugelrohr distillation (80° C., 0.8 mm Hg) gave a yield of 26.26 g (97%) of the named product.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1.FC(F)(F)C(F)(F)C(F)(F)C([O-])=O.[Rh+3].[Rh+3].FC(F)(F)C(F)(F)C(F)(F)C([O-])=O.FC(F)(F)C(F)(F)C(F)(F)C([O-])=O.FC(F)(F)C(F)(F)C(F)(F)C([O-])=O.FC(F)(F)C(F)(F)C(F)(F)C([O-])=O.FC(F)(F)C(F)(F)C(F)(F)C([O-])=O>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=Cc1ccc([Si](C)(C)C)cc1)N=[N+]=[N-]
Agent: [Rh+3]
Agent: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccc([Si](C)(C)C)cc2[nH]1
Temperature: 70 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
0.17 g (0.16 mmol) of the dirhodium heptafluorobutyrate dimer complex is added to a solution of 1.0 g (3.14 mmol) of ethyl 2-azido-3-(4-trimethylsilylphenyl)propenoate obtained in stage 1.1, in 20 ml of dry toluene, maintained under an inert atmosphere. The reaction mixture is then stirred for 12 h at 70° C. After a return to ambient temperature, the reaction mixture is filtered through silica gel, elution being carried out with ethyl acetate. The filtrate is subsequently concentrated under reduced pressure. The residue is purified by silica gel column chromatography, elution being carried out with a mixture of heptane and dichloromethane. 0.61 g of the expected product is isolated in the form of a beige powder.
Reaction SMILES: [Li+].[OH-].[OH:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.CCOC(C)=O>O.C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(C#CCCCO)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(C#CCCCO)cc1
Temperature: 42 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
LiOH (2 g, 83 mmol) in H2O (30 mL) was added dropwise to a stirring solution of Intermediate 20 (2 g, 9.2 mmol) in THF (30 mL). The resulting mixture was stirred at 42° C. for 4 h. After cooling, water (100 mL) and EtOAc (200 mL) were added. The mixture was extracted with EtOAc. The organic layer and the H2O layer were independently neutralized with 1N HCl. The aqueous layer was extracted with EtOAc and the combined organic layers dried over MgSO4 (s). The material was concentrated by rotary evaporation and the crude solid was purified by trituration with EtOAc and hexanes to give the title compound as a white powder (1.75 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 13.05 (brs, 1H), 7.88 (dd, 2H, J=8.5, 1.5 Hz), 7.47 (dd, 2H, J=8.5, 1.5 Hz), 4.55 (brs, 1H), 3.50 (t, 2H, J=5.5 Hz), 2.50 (m, 2H), 1.68 (m, 2H); ES/MS calcd. for C12H1O3+205.1. found m/z=205 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:14]([C:13]4[CH:12]=[CH:11][C:10]([C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:19])([CH3:8])[CH3:9])=[CH:18][CH:17]=4)=[O:16])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(C(C)(C)N3CCCS3(=O)=O)cc2)CC1
Yield: 39.7 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (170 mg) described in Preparation Example 39 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (156 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (115 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(N(CC)CC)C.Cl>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Yield: 82.5 %

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (440 mg; 2.2 mmol), 2-chloro-5-nitro-pyridine (316 mg; 2.0 mmol), and triethylamine (420 μL; 3.0 mL) is dissolved in tetrahydrofuran (6 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 6 hours at 120° C. The reaction mixture is then treated by water (10 mL) and the pH of the aqueous phase is set to 4-5 by the addition of aqueous 1N hydrochloric acid. The aqueous phase is then extracted with dichloromethane (2×20 mL), the combined organic layers are washed with brine (10 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude residue is then purified by column chromatography on silica gel (dichloromethane:ethyl acetate 1:0 and then 5:1) to afford the desired product (533 mg; 1.65 mmol).
Reaction SMILES: Cl[S:2][C:3]1C=CC=C[C:4]=1[C:5](Cl)=[O:6].[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([N:17]2[C:5](=[O:6])[CH2:4][CH2:3][S:2]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)c1ccccc1SCl
Reactant: NC1CCCC1
Product: O=C1CCSN1C1CCCC1

Procedure:
This was prepared in analogous manner to that described in Example 17 except using 2-chlorosulphenylbenzoyl chloride (5.175 parts, 0.025M) and cyclopentylamine (8.52 parts, 0.1M ex Aldrich). The product was obtained as a yellow oil (5.9 parts) which was recrystallised form hexane mp 87-88° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[C:8]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20](O)=[C:15]3[CH:14]=[N:13]2)=[CH:9][S:10][CH:11]=1>>[Cl:3][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([C:8]3[C:7]([CH3:6])=[CH:11][S:10][CH:9]=3)[N:13]=[CH:14][C:15]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cscc1-n1ncc2c(O)ncnc21
Product: Cc1cscc1-n1ncc2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Phosphoryl trichloride (4.2 mL, 45 mmol) was added in one portion to 1-(4-methylthiophen-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate BF2) (700 mg, 3.01 mmol). The resulting suspension was heated to 100° C. to give a solution and stirred for 2 hours. The mixture was evaporated and ice added to the residue and stirred for 30 minutes. It was then filtered and the solids washed with water (3×10 mL). The crude product was dissolved in ethyl acetate (40 mL), dried with MgSO4, filtered and evaporated to give the product (700 mg, 93%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:7][CH:6]=1.[C:26]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27]1.C([O-])(=O)C.[Na+]>CN(C=O)C>[ClH:1].[C:30]([CH2:29][CH2:28][CH2:27][C:26]([NH:3][CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:24])[NH2:25])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:7][CH:6]=1)=[O:33])([OH:32])=[O:31]
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Reactant: O=C1CCCC(=O)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCCC(=O)O)o3)ccc2c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To 8 g of 6-amidino-2-naphthyl 5-aminomethyl-furan-2-carboxylate dihydrochloride, 3.6 g of glutaric anhydride and 1.72 g of anhydrous sodium acetate was added 50 ml of DMF, and the resulting mixture was stirred at 20° C. for 20 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br.O>C(OCC)C>[Br:16][CH2:10][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: O=C(CBr)c1c(F)cccc1F
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)ethanone (10.0 g) in diethyl ether (50 mL) was added anhydrous aluminum chloride (86 mg) and the mixture was stirred for 5 min. Bromine (3.3 mL) was added dropwise at 10-15° C. After stirring at room temperature for 2 hr, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 15.2 g, about 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:12]([CH3:26])[C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NN=C2c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1N=C(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C

Procedure:
To a solution of racemic mixture of 4-Oxo-1-phenyl-2,3,7-triaza-spiro[4.5]dec-1-ene-7-carboxylic acid tert-butyl ester (150 mg, 0.45 mmol) in THF (3 ml) under nitrogen at −78° C. was added 1M LiHMDS solution in THF (0.55 ml, 0.55 mol). The reaction mixture was allowed to warm to RT for 30 mins before cooling back to −78° C. and adding 2M MeI in THF solution (0.45 ml, 0.9 mmol). The reaction mixture was left to warm to RT overnight. The mixture was diluted with EtOAc (10 ml) and washed with brine (20 ml). The aqueous phase was extracted with a further EtOAc (10 ml). The organics portions were combined, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([O:22][CH2:23][CH3:24])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])=[C:4]([F:25])[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][C:4]=2[F:25])[O:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)#[N:21]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccccc1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2)cc1F

Procedure:
In analogy to example 247.1, (RS)-2-(4-bromo-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide was reacted with phenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-biphenyl-4-yl)-2-ethoxy-acetamide. Yellow solid. MS 407.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH:13][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: Clc1cc(Cl)c(Cl)nn1
Solvent: CCO
Product: C=CCNc1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 91.7 g of 3,4,6-trichloropyridazine in 1000 ml of ethanol is added slowly with cooling 85.9 g of allylamine. After stirring 2 hours at room temperature, the mixture is cooled and the resultant precipitate 3,6-dichloro-4-allylamino pyridazine is collected by filtration. Concentration of the filtrate to 200 ml gives a second crop and concentration to 100 ml gives a third crop; m.p. 95° to 98°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.C(O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(COc1ccc(C(=O)Nc2ccc(F)cc2)cn1)OCCc1ccccc1
Yield: 4.2 %

Procedure:
A solution of [5-(4-fluoro-phenylcarbamoyl)-pyridin-2-yloxy]-acetic acid methyl ester (0.020 g, 0.66 mmol), phenethyl alcohol (0.078 mL, 0.66 mmol) and sulfuric acid (1 drop) in toluene (3 mL) was heated at reflux. After 4 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by trituration using ethyl acetate/hexanes gave 0.011 g (42%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s 1H); 8.65 (m, 1H); 8.23 (m, 1H); 7.74 (m, 2H); 7.01-7.27 (m, 8H); 4.94 (s, 2H); 4.27 (m, 2H); 2.85 (m, 2H); MS (EI) m/z 393.03 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].Cl[C:20]1C=CC(S(C(C)C)(=O)=O)=C[C:21]=1C(O)=O.N1CCCC1>>[CH2:1]([S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:20][CH3:21]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: CCCS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Yield: 63 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(propane-2-sulfonyl)-benzoic acid and pyrrolidine and obtained in 63% yield. MS (m/e): 296.2 (MH−, 100%).