Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)C[C@H](CC(C)C)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@H](CC(=O)O)CC(C)C)cc3)ccc2C(C)(C)C)c1
Reaction time: 19 h
Yield: 72.2 %

Procedure:
To a stirred solution of 45.2 (0.048 g, 0.09 mmol) in THF (2.00 mL, 0.10 mmol) and EtOH (2.00 mL, 0.10 mmol) at 23° C. was added a 1 M solution of sodium hydroxide (1 mL, 1 mmol). The reaction was then stirred for 19 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 45 (32 mg, 71% yield) as a colorless oil. MS ESI (neg.) m/e: 983.5 (M−H)+, 491.2 (M−H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[O:5]
Reactant: OCCNCCO
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CCO)CCO

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and diethanolamine.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:24][CH:25]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Temperature: 120 °C
Yield: 88.7 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (65 mg, 0.116 mmol) in a 2:1 mixture of tetrahydrofuran and methanol (1.5 mL) was added 1N sodium hydroxide (0.175 mL, 0.175 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated and water was added followed by 0.175 mL of 1N HCl. The solution was extracted twice with ethyl acetate. The combined organic phases were washed one time with brine and concentrated. Ether was added and the solution was again concentrated to dryness to afford the title compound as a white solid (56 mg, 89%). 1H-NMR (DMSO-d6,) δ 13.14 (s, 1H), 8.88 (d, J=9 Hz, 1H), 8.20-8.16 (m, 2H), 8.09 (d, J=9 Hz, 1H), 7.90 (d, J=9 Hz, 1H), 7.69-7.49 (m, 6H), 6.90 (d, J=9 Hz, 2H), 4.83 (s, 2H), 4.00 (quintet, J=9 Hz, 1H), 2.43-2.34 (m, 4H), 2.10-1.92 (m, 2H). HRMS C31H23Cl2NO4 m/z 544.10769 (M+H)+Cal; 544.10747 (M+H)+Obs.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH:15]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:20][CH:21]=[C:22]([CH:24]3[CH2:26][CH2:25]3)[CH:23]=2)[CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:30]2[CH2:31][CH2:32][N:27]([C:19]3[C:18]([CH:15]4[CH2:16][CH2:17]4)=[CH:23][C:22]([CH:24]4[CH2:26][CH2:25]4)=[CH:21][N:20]=3)[CH2:28][CH2:29]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 73 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 38 and using 4-bromo-2-methanesulfonylbenzoic acid (2.29 g) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (2 g) described in Preparation Example 62, the title compound (3.02 g) was obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:19][CH3:20])([CH3:18])[C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:8][CH:7]=1.O.[NH2:23][NH2:24]>C(O)C>[CH2:19]([C:4]1([CH3:18])[C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:8][CH:7]=2)=[N:24][NH:23][C:3]1=[O:2])[CH3:20]
Reactant: CCC(C)(C(=O)OC)C(=O)c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCC1(C)C(=O)NN=C1c1ccc(-n2ccnc2)cc1

Procedure:
A solution of 3.8 g of α-ethyl-4-(1H-imidazol-1-yl)-α-methyl-β-oxobenzenepropanoic acid methyl ester, 2.0 g of hydrazine hydrate and 25 ml of ethanol was refluxed for 20 hours. The ethanol is removed and the residue is treated with ether and water. Filtration of the solid gives after recrystallization from ethyl acetate, 2.7 g of a crystalline solid, mp 86°-88° C.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[C:22]([Cl:35])=[CH:21][C:20]=2[O:36][CH2:37][CH:38]=[CH2:39])[O:7][C@@H:6]1[CH2:40][O:41]C(=O)C)(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[CH2:37]([O:36][C:20]1[CH:21]=[C:22]([Cl:35])[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=2)=[CH:24][C:19]=1[C@H:8]1[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:40][OH:41])[O:7]1)[CH:38]=[CH2:39]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (12, 4 g, 6.32 mmol) from Step 1 in methanol (90 mL) was added sodium methoxide (25% in methanol, 9 mL) and the reaction mixture was stirred at ambient temperature for 5 h. The solution was cooled to 0° C. prior to neutralizing with acetic acid (4.5 mL). After removal of organic volatiles under reduced pressure, the residue was diluted with ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sodium hydrogen carbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound (13) as a white solid which was used without further purification.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.CC(C)([O-])C.[Na+].Cl[C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1>COCCOC>[O:6]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:1][O:7][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1
Reactant: OCC1CCCO1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1nc(OCC2CCCO2)nc2c1ncn2C1CCCCO1
Temperature: 110 °C
Yield: 54.2 %

Procedure:
Tetrahydrofurfuryl alcohol (4.09 g) was diluted with 1,2-dimethoxyethane (20 mL). To this solution was added sodium tert-butoxide (3.84 g) gradually. The resultant reaction mixture was stirred until homogeneous (orange solution) before 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.53 g) was added. The reaction mixture was then heated to 110° C. (external) overnight under nitrogen. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL, 3 times). The organic layer was separated, combined and then dried by passing through a hydrophobic frit. This was evaporated under reduced pressure and the resultant material was then purified by silica chromatography eluting with 0-100% ethyl acetate: cyclohexane followed by methanol. An ISCO pump fault was detected whilst eluting with methanol, this line carried ethyl acetate previously and it was not known if the fault existed when eluting with ethyl acetate: cyclohexane. The appropriate fractions were evaporated to give the title compound as a solid (1.7258 g). This material was used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH2:10]([C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([S:21]([NH:24][CH3:25])(=[O:23])=[O:22])=[C:14]([NH:26][CH2:27][CH2:28][CH3:29])[C:13]=1[N+:30]([O-:32])=[O:31])[CH3:11].N1C=CC=CC=1>ClCCl>[CH2:10]([C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([S:21]([N:24]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:25])(=[O:23])=[O:22])=[C:14]([NH:26][CH2:27][CH2:28][CH3:29])[C:13]=1[N+:30]([O-:32])=[O:31])[CH3:11]
Reactant: CCCNc1c(S(=O)(=O)NC)cc([N+](=O)[O-])c(CC)c1[N+](=O)[O-]
Reactant: ClSc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCNc1c(S(=O)(=O)N(C)Sc2ccc(Cl)cc2)cc([N+](=O)[O-])c(CC)c1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
A 2.2 g (0.012 mol) sample of p-chlorophenylsulfenyl chloride was added dropwise to a cooled (-5° C. to 0° C.) solution of 3.5 g (0.1 mol) 4-ethylpropylamino-N-methyl-3,5-dinitrobenzenesulfonamide and 1.1 g (0.014 mol) pyridine in 25 ml dichloromethane. The reaction was stirred for 20 minutes and then diluted with 50 ml dichloromethane, washed with water, washed with aqueous sodium bicarbonate solution, and dried over magnesium sulfate. The dichloromethane was then evaporated under reduced pressure to give a solid residue. Recrystallization from ethanol gave the product as red-orange plates, m.p. 89°-91° C. Elemental analysis for C18H21ClN4O6S2 showed: % S, calc. 13.1, found 13.3; % Cl, calc. 7.3, found 7.8.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(=O)(=O)(O)O>O.CC(C)=O>[C:13]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
108 g of L-glutamine was dissolved in 343 g of water and 102 g of aqueous 27% sodium hydroxide solution, and cooled to 10° C. 138 g of acetone was added to it, and 152 g of lauroyl chloride and 108 g of aqueous 27% sodium hydroxide solution were dropwise added thereto. The acylation liquid was diluted with 300 g of water, then neutralized with 35 g of 75% sulfuric acid and filtered to obtain a white powdery substance, N-lauroyl-L-glutamine. 72.4 g of thionyl chloride was dropwise added to 424 g of isopropyl alcohol, then 100 g of N-lauroyl-L-glutamine was added thereto and reacted at room temperature for 8.5 hours. The reaction liquid was added to 2.0 L of water to precipitate the intended product, and this was taken out by filtration to obtain a crude product. This was recrystallized repeatedly three times with acetone to obtain 59.1 g of N-lauroyl-L-glutamine isopropyl ester.
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)(=[O:3])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[NH:23][NH2:24])[CH:17]=[C:18]([F:20])[CH:19]=1>CO>[F:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[NH:23][N:24]=[C:6]([OH:8])[C:5]2[CH:9]=[CH:10][CH:11]=[N:12][C:4]=2[C:1](=[O:3])[CH3:2])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: CC(=O)c1ncccc1C(=O)O
Reactant: NNC(=O)Nc1cc(F)cc(F)c1
Solvent: CO
Product: CC(=O)c1ncccc1C(O)=NNC(=O)Nc1cc(F)cc(F)c1

Procedure:
To 50 mg of 2-acetylnicotinic acid are added 56 mg of 4-(3,5-difluorophenyl)semicarbazide and 1 mL of methanol. After a minute of stirring the product begins precipitating from the solution. After stirring overnight (15 h) the stir vane is removed and rinsed with 0.2 mL of methanol. The reaction mixture is centrifuged and the supernatant solution removed. In the same way the solid is rinsed with methanol (3×0.5 mL) and ether (1×0.5 mL). The solid is dried in vacuo with heating to give 2-acetylnicotinic acid 4-(3,5-difluorophenyl)semicarbazone (also known as 2-[methyl-{[(3,5-difluorophenylamino)carbonyl]hydrazono}methyl]-3-pyridine-carboxylic acid), m.p. 186° (compound 31, Table A).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[C:23]1([CH2:29][CH2:30][NH2:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:30]([NH:31][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: NCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCc3ccccc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-phenylethanamine hydrochloride (207.8 mg, 1.32 mmol, 3.00 equiv), potassium carbonate (304.4 mg, 2.21 mmol, 5.00 equiv), N,N-dimethylformamide (2 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 120 mg (71%) of methyl 3-(phenethylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:16])[O:21][CH2:20][CH2:19][O:17]2)=[CH:11][C:10]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc(OCc3ccccc3)c(F)c2)OCCO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(4-(benzyloxy)-3-fluorophenyl)ethanone 22 (23.8 g, 97.5 mmol), ethylene glycol (16.4 mL, 293 mmol), p-TsOH (930 mg, 4.88 mmol) and toluene (400 mL) was stirred under reflux conditions for 4 days, azeotropically removing water with a Dean-Stark trap. The mixture was cooled to room temperature and quenched by addition of saturated sodium bicarbonate solution (200 mL). The aqueous phase was back-extracted with toluene (3×200 mL). The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 28.7 g (103%) of crude 23 as a yellow solid. Crude 23 was used without further purification. 1H NMR (CDCl3) δ: 7.39 (m, 5H), 7.22 (dd, 1H), 7.16 (dd, 1H), 6.95 (t, 1H), 5.12 (s, 2H), 4.12 (dd, 2H), 3.77 (dd, 2H), 1.62 (s, 3H). LCMS m/z=289.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]P(=O)(OCC)OCC)=[CH:3][CH:2]=1.C(O[K])(C)(C)C.[CH:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=2)[NH:26][N:25]=1)=O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:22]/[C:24]2[C:32]3[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=3)[NH:26][N:25]=2)=[CH:5][CH:6]=1
Reactant: CCOP(=O)(Cc1ccncc1)OCC
Reactant: N#Cc1ccc2c(C=O)n[nH]c2c1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 82 %

Procedure:
Diethyl pyridin-4-ylmethylphosphonate was redissolved in DMF (25 mL) and cooled to 0° C. tBuOK (3.36 g, 30 mmol) was added portion wise over 2 min and the reaction mixture turned dark brown red. After stirring for 2 min at 0° C., a solution of 3-formyl-1H-indazole-6-carbonitrile (1.71 g, 10 mmol) in DMF (15 mL) was added dropwise by pipette over 5 min. The resulting mixture was stirred for 40 min at 0° C. before quenching with ice, 2N HCl (20 mL) and H2O (20 mL). After stirring for 10 min at rt, the reaction mixture was carefully basified with sat. NaHCO3 to pH about 8 and copious amounts of yellow precipitate formed. The solid was collected by suction filtration and rinsed with H2O. After dying under high vacuum, 2.016 g (82%) of title compound was obtained as beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H, NH), 8.60-8.54 (m, 2H), 8.43 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 7.93 (d, J=16.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H, partially overlapping with the doublet at 7.55 ppm), 7.55 (d, J=16.0 Hz, 1H, partially overlapping with the doublet at 7.58 ppm); MS ESI 250.0 [M+H]+, calcd for [C15H11N3O+H]+ 250.1.
Reaction SMILES: C(OC([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](C2CCN(C(OCC)=O)CC2)=[CH:7]1)=O)C.[OH-].[K+]>C(O)(C)C>[N:11]1([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:6][CH:7]=2)[CH2:12][CH2:13][CH2:14][CH2:9][CH2:10]1
Reactant: CCOC(=O)N1CCC(c2cn(C(=O)OCC)c3ncccc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1cnc2[nH]cc(N3CCCCC3)c2c1

Procedure:
14.67 g (42.0 mmol) of 3-(1-ethoxycarbonyl-piperidin-4-yl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid ethyl ester were added to a solution of 40.32 g (720 mmol) of potassium hydroxide in 630 ml of isopropanol. The mixture was refluxed for 20 hours. The solvent was distilled off and cold water was added. This solution was acidified with concentrated hydrochloric acid and then basified with 8 N aqueous sodium hydroxide solution. This aqueous solution was extracted twice with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure affording 4.66 g (48% of yield) of the expected product as an oil.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[C:30](=[O:37])[CH2:31][C:32]([CH2:35][OH:36])=[N:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:21]([O:28][C:29]1[C:30](=[O:37])[CH2:31][C:32]([CH2:35][O:36][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC(CO)=NC=C1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)=NC=C1OCc1ccccc1
Temperature: 95 °C
Yield: 42.8 %

Procedure:
4-Dimethylaminopyridine (17.55 g) and trityl chloride (40.5 g) are added to a solution of 5-benzyloxy-2-hydroxymethyl-4-pyridone (30.2 g) in dry dimethylformamide and the mixture stirred and heated at 95° C. for 2 hours. After cooling the mixture is poured into iced-water (800 mL) and the precipitate collected, washed with water (2×500 mL) and sucked dry. The solid is boiled with methanol (500 mL) and after cooling the solid is collected, washed with methanol (200 mL) and diethyl ether (2×100 mL) and dried at 80° C. to give 5-benzyloxy-2-trityloxymethyl-4-pyridone (26.5 g) as a white solid, m.p. 233-5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10].[OH:21]OS([O-])=O.[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([F:11])[F:10]
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(Cl)c2)OC1(C)C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc(OC(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 4-bromo-2-chloro-1-(difluoromethoxy)benzene (Preparation 70, 0.83 g, 3.2 mmol) in THF (16 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.90 g, 3.6 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), and potassium acetate (0.98 g, 9.7 mmol) under a nitrogen atmosphere and the mixture heated at reflux for 2 hours. The reaction mixture was then concentrated in vacuo, the resulting residue filtered through silica gel pad with arbocel and washed EtOAc. The filtrate was concentrated in vacuo to yield a crude product of 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A solution of crude 2-[3-chloro-4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 3.3 mmol) in acetone (10 mL) was added to an aqueous oxone solution (2.6 g, 3.9 mmol, 10 mL) dropwise with stirring at 0° C. for 1 hour. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) and the organic layer was washed with brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 0 to 40% EtOAc in heptane to afford the title compound as a pale brown oil (0.53 g, 82%):
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.C([O-])([O-])=O.[K+].[K+].[Br:20][CH2:21][CH2:22]Br>C(#N)C>[Br:20][CH2:21][CH2:22][N:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: BrCCBr
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(=O)OC)n(CCBr)n1
Reaction time: 12 h

Procedure:
A solution of this ester (5.0 g, 27.2 mmol) in 150 ml of anhydrous acetonitrile was treated with K2CO3 (5.2 g, 40.0 mmol) and 1,2-dibromoethane (25.0 ml, 291 mmol). The resulting mixture was heated to reflux under argon. After 25 min the reaction suspension was cooled, filtered and the filtrate evaporated to dryness at reduced pressure and placed on a high vacuum line for 12 h. The resulting white solid was recrystalized from hexane to give 3-2 as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[N:27]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([C:13]4[C:14]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:15][O:16][C:17]=4[CH3:18])=[N:11][N:12]=3)=[C:4]([O:25][CH3:26])[CH:3]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: c1c[nH]cn1
Product: COc1cc(-n2ccnc2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 36 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using imidazole instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 82 mg, 36%) which was obtained as an off-white solid. MS: m/e=400.2 [M+H]+.