Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8]C1C=C(C=CC=1OCCC)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][CH3:33])[CH2:25][OH:26].C(Cl)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:23]1[CH:22]=[C:29]([O:30][CH2:31][CH2:32][CH3:33])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOc1ccc(CO)cc1O
Reactant: CCCOc1ccc(C=O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCc1ccccc1
Product: CCCOc1ccc(C=O)c(OCc2ccccc2)c1

Procedure:
2,4,6-tribenzyloxyacetophenone is obtained by the common procedure of reacting 2,4,6-trihydroxyacetophenone with excess benzyl chloride and excess potassium carbonate in dimethylformamide and giving the reaction mixture an aqueous work up. 3-benzyloxy-4-n-propoxybenzaldehyde is similarly prepared from 3-hydroxy-4-n-propoxybenzyl alcohol, excess benzyl chloride and excess potassium carbonate. A warm solution of 2.19 g of the 2,4,6-tribenzyloxyacetophenone and 1.35 g of the benzyloxy-4-n-propoxybenzaldehyde is prepared in 10 ml of absolute ethanol. 15 Milliliters of warm aqueous 60% potassium hydroxide is added all at once. The mixture is stirred and a yellow solid product is formed. 16 Milliliters of absolute ethanol is added and the mixture is added to 300 ml of water and extracted three times with ethyl acetate. The extracts are dried and concentrated to yield 3.2 g of a solid, which is recrystallized to yield 2.6 g (75% yield) of 2,4,6,3'-tetrabenzyloxy-4'-n-propoxychalcone. ##SPC5## 1.38 Grams of this material is dissolved in about 50 ml of ethyl acetate and 200 mg of 5% palladium on charcoal is added. The reaction flask is flushed with hydrogen and then the mixture is stirred under hydrogen at room temperature for about 35 hours. The product is checked by thin layer chromatography and observed to contain essentially a single product. The reaction mixture is filtered and concentrated to yield 0.66 g of a colorless oil, which by NMR is determined to be 2,4,6,3'-tetrahydroxy-4'-n-propoxy dihydrochalcone, ##SPC6##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[H-].[Na+].[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O1CCCC1>[CH2:18]([O:17][C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH:11]=[O:12])=[CH:6]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(C(=O)OCc2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-chloro-3-formylindole (5.00 g) in tetrahydrofuran (135 ml) was added sodium hydride (60% oil suspension, 3.53 g). The mixture was stirred for 20 minutes at room temperature. Carbobenzoxychloride (6.64 ml) was added to the mixture. After being stirred for 1 hour at room temperature, the whole was poured into ice water. The mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solution was concentrated to give a residue, which was subjected to silica gel chromatography. Elution with hexane-ethyl acetate (5:1) provided 1-benzyloxycarbonyl-5-chloro-3-formylindol (5.74 g) as a crystal.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[C:11]([N:28](C(O)C)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([N:28]([CH2:2][CH:1]=[O:5])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCCCCCCCCN(CC=O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (12.24 ml) and methylene chloride (50 mL) at −35 to −45° C. was added DMSO (14.75 g) in methylene chloride (25 mL) over 20 minutes. The reaction mixture was stirred for 10 minutes at −35 to −45° C. A solution of N-Fmoc-decylaminoethanol (20.0 g) in methylene chloride (70 mL) was added over 25 minutes and then stirred 40 minutes at −35 to −45° C. Triethylamine (21.49 g) was then added and the mixture stirred for 30 minutes at −10 to −20° C. The reaction mixture was quenched with water (120 mL) followed by concentrated sulfuric acid (20.0 g) while maintaining the internal temperature at 0-5° C. The organic layer was isolated and washed with 2% sulfuric acid (100 mL) followed by water (2×100 mL). The organic solution was distilled under vacuum at 60° C. to about 100 mL. Heptane (100 mL) was added, the temperature of the oil bath raised to 80° C. and the distillation was continued until the residual volume was 100 mL. More heptane (100 mL) was added and the distillation repeated to a volume of 100 mL. The heating bath was replaced with a cold water bath at 15° C. The bath was cooled slowly to 5° C. over 20 minutes to start the precipitation of the product. The slurry was then cooled to −5 to −10° C. and the slurry was stirred for 2 hours. The solid was then collected on a Buchner funnel and washed with cold (−5° C.) heptane (2×15 mL). The wet solid was dried in vacuo to yield the aldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.[Br:13][C:14]1[S:18][C:17]2=[N:19][C:20]([C:22](O)=[O:23])=[CH:21][N:16]2[CH:15]=1>>[Br:13][C:14]1[S:18][C:17]2=[N:19][C:20]([C:22]([NH:12][C:9]3([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH2:10][CH2:11]3)=[O:23])=[CH:21][N:16]2[CH:15]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NC1(c2cc(F)ccc2F)CC1
Product: O=C(NC1(c2cc(F)ccc2F)CC1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using 1-(2,5-difluorophenyl)cyclopropanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17](Br)[CH:16](Br)[C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]1=2)=[O:12])=[O:4].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]#[C:16][C:15]2[CH:27]=[CH:28][CH:29]=[CH:30][C:14]1=2)=[O:12])=[O:4]
Reactant: O=C(CCCCCNC(=O)C(F)(F)F)N1Cc2ccccc2C(Br)C(Br)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCCCCNC(=O)C(F)(F)F)N1Cc2ccccc2C#Cc2ccccc21
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Pyridine hydrobromide perbromide (0.948 g, 2.97 mmol) was added to a solution of 3 (1.05 g, 2.70 mmol) in CH2Cl2 (4 ml) at room temperature, and the reaction mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with 5% aqueous hydrochloric acid (20 mL), dried over MgSO4, and solvent removed under vacuum. The residue was passed through a short pad of silica gel (CH2Cl2) to give 1.2 g of crude N-(trifluoroacetamidohexanoyl)-5,6,11,12-tetrahydro-11,12-dibromodibenzo[b,f]azocine (4) as an oil. Solution of crude 4 (1.2 g, 2.082 mmol) in THF (5 mL) was added to a solution of potassium t-butoxide (0.584 g, 5.21 mmol) in THF (10 ml) at room temperature, the reaction mixture was stirred for 1 hour, diluted with ethyl acetate (20 mL), washed with 5% aqueous hydrochloric acid, brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by chromatography (hexanes:ethyl acetate, 2:1 to 1:1) to afford 0.76 g (1.834 mmol, 88%) of 5 as brown oil. 1H NMR: δ 7.68 (d, J=7.6 Hz, 1H), 7.45-7.21 (m, 7H), 6.79 (br s, 1H), 5.16 (d, J=14.4 Hz, 1H), 3.67 (d, J=13.6 Hz, 1H), 3.22-3.14 (m, 1H), 3.11-3.02 (m, 1H), 2.24-2.16 (m, 1H), 1.41-1.22 (m, 4H), 1.11-0.9 (m, 2H); MS: m/z 414 [M+]. Calcd for C23H21F3N2O2 414.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C1C=CC=CC=1>[Pd]>[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CC1COCCN1Cc1ccccc1)C(=O)OCC
Agent: [Pd]
Product: CCOC(=O)C(CC1COCCN1)C(=O)OCC
Yield: 89 %

Procedure:
Diethyl 2-((4-benzylmorpholin-3-yl)methyl)malonate (1 g, 2.86 mmol) was reacted with Pd/C (10%, 0.1 g) according to the procedure as described in Example 34, Step C to give the title compound as colorless oil (0.66 g, 89%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[Mg].II.N([P:18]([Cl:20])Cl)(CC)CC>CCOCC.C1COCC1>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[P:18]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])[Cl:20]
Reactant: CCN(CC)P(Cl)Cl
Reactant: Cc1ccc(Br)c(C)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(P(Cl)c2ccc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.92 ml (2161 mmol) of 4-bromo-1,3-dimethylbenzene in 3 ml of Et2O were added at 0° C. to a suspension of 0.5 g (20.56 mmol) of magnesium turnings in 7 ml of THF and 7 ml of Et2O and also a crystal of iodine. The mixture was heated to room temperature, stirred further overnight and slowly added dropwise at 0° C. to a solution of 1.5 ml (10.31 mmol) of Et2NPCl2 in 8 ml of THF. The mixture was heated to room temperature and the solvent was subsequently removed under reduced pressure. After adding 60 ml of hexane, the mixture was filtered through Celite under argon and admixed with hydrogen chloride for 1 hour. After degassing, the resulting solids were filtered off under argon and dried. Yield: 1.4 g (58.3% of theory). 1H NMR (400 MHz, CDCl3) δ, 7.40 (d, Jmeta=4.5 Hz, 2H, arom.), 7.2 (m, 4H, arom.), 2.5 (d, JPH=2.0 Hz, 6H, CH3), 2.4 (s, 6H, CH3). 31P NMR (161.974 MHz, CDCl3) δ, 75.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(=O)c1ccc(N)cc1

Procedure:
A solution of 10 g. of ethyl p-nitrophenylglyoxylate in 10.0 ml. of ethanol is hydrogenated at room temperature and atmospheric pressure with 10% palladium-on-carbon catalyst until the starting material has disappeared by thin-layer chromatographic analysis. The system is purged with nitrogen, the reaction mixture is filtered through a celite pad and the solvent is evaporated. Recrystallization of the residue provides ethyl p-aminophenylglyoxylate.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:5]([NH:1][C:2]([NH2:4])=[S:3])(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: NC(N)=S
Reactant: CC(C)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)C(=O)NC(N)=S
Temperature: 25 °C
Yield: 30.8 %

Procedure:
Thiourea (152 g, 2 mol) was dissolved in toluene (1520 mL). To the solution was added isobutyryl chloride (213 g, 2 mol) under mechanical stirring. The reaction mixture was refluxed for 3 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The filtrate was concentrated to dryness. The yellow solids were collected by filtration, washed with petroleum ether (100 mL×3) to appear white, dried in vacumm to give the desired product 11A (90 g, 30% yield) as a white solid (mp: 114˜116° C.).
Reaction SMILES: Br[C:2]([Br:5])([CH3:4])C.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K].[CH3:18]N(C=O)C>>[Br:5][CH2:2][CH2:4][CH2:18][N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11]
Reactant: CN(C)C=O
Reactant: CC(C)(Br)Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCCBr
Temperature: 90 °C
Reaction time: 17 h
Yield: 49 %

Procedure:
To a solution of dibromopropane (0.61 mL, 6.0 mmol) in DMF (8 mL) was added potassium phthalimide (0.2756 g, 1.5 mmol), and was stirred at 90° C. for 17 hours. The mixture was concentrated, 1N NaOH (10 mL) was added, and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with water (1×15 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (4:1 hexanes-EtOAc) provided 0.1977 g (49%) of 2-(3-bromo-propyl)-isoindole-1,3-dione as a white solid. 1H NMR(CDCl3) δ 2.21-2.30 (m, 2H), 3.41 (t, 2H, J=6.0 Hz), 3.83 (t, 2H, J=6.0 Hz), 7.69-7.75 (m, 2H), 7.82-7.86 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:13]1([CH3:26])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O:24][NH2:25])(=[O:23])=[O:22].CCOCC>C(Cl)Cl>[C:13]1([CH3:26])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([O-:24])(=[O:23])=[O:22].[N:1]1([CH2:6][C:7]2[CH:8]=[N+:9]([NH2:25])[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: c1cncc(Cn2cccc2)c1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1cccc(Cn2cccc2)c1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
To an ice cooled solution of 3-((1H-pyrrol-1-yl)methyl)pyridine (2.94 g, 18.58 mmol) in 25 mL of dry methylene chloride was added drop wise to O-mesitylenesulfonylhydroxylamine (4.0 g, 18.58 mmol) in 10 mL of dry methylene chloride over 5 min with stirring. The reaction was stirred at 0° C. for 3 hrs. 60 mL of ether was added and the suspension filtered. The precipitate was recrystallized from ethyl acetate-methanol (5:1 v/v) to give 3-((1H-pyrrol-1-yl)methyl)-1-aminopyridinium mesitylenesulfonate (8) in 57.5% yield. The N-Aminopyridinium salt (1.5 g, 4.02 mmol) in 30 ml of anhydrous tetrahydrofuran (THF) containing triethylamine at 70° C. was stirred for 5 min before benzenesulfonyl chloride (0.78 g, 4.42 mmol) was added. The mixture was allowed to proceed for 12 hrs. 70 mL of saturated sodium bicarbonate (NaHCO3) arrested the reaction. The product (10a) was extracted twice with 100 ml of chloroform and dried over anhydrous sodium sulfate, followed by filtration. Solvent was removed in vacuo to give the crude product, which was further purified by column chromatography (2.5×22 cm) on silica gel (200-425 mesh) using ethyl acetate:methanol (9:1 v/v) as eluent. The resultant product was obtained as a light yellow crystalline solid in 43.9% yield.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:14](=[O:16])[CH3:15])[CH2:9][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:6]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)#[N:53].CO.C(Cl)Cl>C(Cl)Cl.O>[C:14]([N:10]1[CH2:11][CH2:12][C:13]2[N:5]([CH2:4][CH:2]([OH:1])[CH2:3][N:63]3[CH2:62][CH2:61][N:60]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=4[C:52]#[N:53])[CH2:65][CH2:64]3)[N:6]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:8]=2[CH2:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Reaction time: 48 h

Procedure:
A solution of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.84 g, 2.30 mmol) in CH2Cl2 (10 mL) was treated with ytterbium(III)triflate (0.29 g, 0.46 mmol) and 1-(2-cyanophenyl)-piperazine (0.75 g, 3.5 mmol) at 25° C. and stirred for 48 h before it was diluted with CH2Cl2 (100 mL) and H2O (50 mL). The organic layer was separated, washed with H2O (2×50 mL), dried over Na2SO4, and concentrated. Column chromatography (silica, 5% MeOH/CH2Cl2) afforded 1.15 g (90%) of light yellow crystals. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.30. MS (electrospray): m/z 553.3 ([M+H]+, C29H31F3N6O2 requires 552.3). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 7.82 and 7.68 (AB pattern, Jab=8.2 Hz, 2H), 7.76 and 7.72 (AB pattern, Jab=8.4 Hz, 2H), 7.60-7.48 (m, 2H), 7.05-7.00 (m, 2H), 4.90 and 4.78 (AB pattern, Jab=16 Hz, 1H), 4.69 (s, 1H), 4.30-3.71 (m, 6H), 3.25 (m, 4H), 3.02-2.75 (m, 4H), 2.70-2.65 (m, 2H), 2.60-2.53 (m, 2H), 2.23 (s, 1.5H), 2.18 (s, 1.5H).
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>O1CCCC1>[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)[OH:22]
Reactant: O=Cc1cccc(F)c1F
Reactant: CCOC(OCC)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ncc[nH]1)c1cccc(F)c1F
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a solution of 1-(diethoxymethyl)-1H-imidazole (1.65 ml, 10.1 mmol) in tetrahydrofuran (15 ml), at −60° C. and under nitrogen, was added n-butyllithium (2.5 M in hexanes, 4.03 ml, 10.1 mmol). The reaction mixture was stirred at −60° C. for 1 h, before addition of 2,3-difluorobenzaldehyde (1.00 ml, 9.2 mmol), and then allowed to warm to room temperature over 18 h. The mixture was concentrated in vacuo and to the residue was added ethyl acetate (50 ml) and hydrochloric acid (3M, 50 ml). The two layers were separated and the aqueous phase was basified with aqueous sodium hydroxide solution (20%) and extracted with ethyl acetate (3×100 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo and the residue was re-crystallised from 2-propanol to give the title compound (1.25 g)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[NH2:21].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[NH:21][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: COC(=O)c1cccnc1N
Reactant: O=C(O)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccnc1NC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solution of 2-pyridyl-acetic acid hydrochloride (310 mg) and 2-amino-nicotinic acid methyl ester (270 mg) (Example 1.1) in dichloromethane (5 ml) was added diisopropylethylamine (0.32 ml). The reaction mixture was stirred at ambient temperature for 20 minutes. To this solution was added 4-dimethylaminopyridine (43 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (“EDAC”) (410 mg). The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between dichloromethane and water. The phases were separated and the organic layer concentrated. The residue was purified by column chromatography on silica gel (eluent: 15% acetone in dichloromethane) to give 2-(2-pyridin-2-yl-acetylamino)-nicotinic acid methyl ester as a yellow solid (86 mg). 1H-NMR (400 MHz, CDCl3): 11.14 (bs, 1H), 8.63-8.64 (m, 1H), 8.58-8.59 (dd, 1H), 8.25-8.27 (dd, 1H), 7.66-7.70 (m, 1H), 7.38 (d, 1H), 7.20-7.23 (m, 1H), 7.05-7.08 (dd, 1H), 4.11 (s, 2H), 3.92 (s, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[NH2:19][NH2:20]>C(O)C>[F:14][C:13]([F:16])([F:15])[C:12]1[C:7]([O:6][CH2:5][C:4]([NH:19][NH2:20])=[O:3])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ncccc1C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)COc1ncccc1C(F)(F)F
Yield: 77 %

Procedure:
As described for example 112a, (3-trifluoromethyl-pyridin-2-yloxy)-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 77%). MS: m/e=236.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9](C)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].[OH-:12].[Na+]>O.COCCOC>[CH3:2][CH:3]1[CH:4]([CH2:5][O:11][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2][OH:1])[O:12]1
Reactant: [OH-]
Reactant: Cc1cccc(O)c1CCO
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1OC1COc1ccccc1CCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 123.7 %

Procedure:
A mixture of 5.04 g (0.033 mole) of 2-(2-hydroxyethyl)-3-methylphenol, 1.33 g (0.033 mole) of sodium hydroxide in 135 ml of water, and 5.00 g (0.033 mmole) of erythro-(1-bromoethyl)oxirane in 25 ml of 1,2-dimethoxyethane was stirred at room temperature for about 72 hours. The mixture was extracted with 5×100 ml of ether. The extract was washed with dilute sodium hydroxide solution, dilute brine and saturated brine, dried over MgSO4 and concentrated in vacuo to give 4.25 g (58%) of 2-methyl-3-[2-(2-hydroxyethyl)phenoxymethyl]oxirane. A 1:1 (v/v) mixture of 1-methylethylamine and water (130 ml) was added to the oxirane and the mixture was heated at reflux for 5 hours, and concentrated in vacuo to dryness. The residue was dissolved in ether, dried over MgSO4 and concentrated to dryness to give 2.90 g of oil. The oil was flash chromatographed on a silica gel column by elution with 3% CH3OH in CHCl3 saturated with ammonia gas to give 0.5 g of product. Conversion to the oxalate salt gave material with m.p. 138°-140° C. (0.5 isopropanol solvate).