Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)Cl.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)CC2CCN(Cc3ccccc3)CC2)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CC(=O)c2cccc(C)c2)CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred mixture of 20.9 parts of 1-(3-methylphenyl)-2-[1-(phenylmethyl)-4-piperidinyl]ethanone, 0.75 parts of sodium carbonate and 150 parts of trichloromethane are added dropwise 8.1 parts of ethyl chloroformate. Upon completion, stirring is continued overnight at room temperature. Water is added to the reaction mixture and the layers are separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 18 parts (91%) of ethyl 4-[2-(3-methylphenyl)-2-oxoethyl]-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[O:10]=[C:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].N1CCCCC1>C1C=CC=CC=1>[C:11](/[C:12](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)/[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:17]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)/C(=C\c1ccc(F)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 4-fluorobenzaldehyde (25.5 g, 0.220 mol), methyl 3-oxobutanoate (21.80 g, 0.220 mol), and piperidine (1.0 mL) in anhydrous benzene (250 mL) was stirred for 10 minutes at room temperature and subsequently refluxed overnight in a Dean-Stark apparatus. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo to afford methyl (2Z)-2-acetyl-3-(4-fluorophenyl)-2-propenoate as a black solid (48.6 g, 99%), which was used for next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Temperature: 50 °C
Reaction time: 20 h
Yield: 109.4 %

Procedure:
N2-Butyl-8-(methyloxy)-9H-purine-2,6-diamine trifluoroacetate (5 g, 14.27 mmol) and potassium carbonate (4.93 g, 35.7 mmol) were suspended in DMF (40 ml) and heated to 50° C. under nitrogen for 30 mins. The mixture was cooled to room temperature, 1-bromo-4-chlorobutane (1.645 ml, 14.27 mmol) was added and stirring was continued at room temperature for 20 hours. The solvent was concentrated under vacuum and the residue was partitioned between DCM (100 ml) and water (100 ml). The layers were separated using a hydrophobic frit and the aqueous phase was re-extracted with DCM (100 ml). The combined organics extracts were concentrated in vacuo and the residue purified by chromatography using a FlashMaster apparatus (100 g silica cartridge) and using a DCM:methanol 0-25% gradient over 40 mins. The desired fractions were combined and concentrated under vacuum to give the impure title compound as a yellow oil (5.1 g).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:2].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:23](=[O:26])([O-])[O-].[K+].[K+]>CO>[CH3:12][O:2][CH:1]([O:26][CH3:23])[C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1cccc2nnsc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(OC)c1cccc2nnsc12

Procedure:
A solution of 3.3 g of 7-formylbenzo-1,2,3-thiadiazole in 50 ml of methanol and 0.2 g of p-toluenesulfonic acid is refluxed for 6 hours in a Soxhlet apparatus charged with a molecular sieve A4. The mixture is then cooled, rendered basic using solid potassium carbonate, filtered through Hyflo and evaporated. The residue is purified on silica gel using hexane/ethyl acetate (1:1), resulting in the title compound of refractive index nD21 =1.5750.
Reaction SMILES: [C:1]1(=[O:20])[N:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[C:4](=[O:15])[C:3]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:2]12.FC(F)(F)C(O)=O>ClCCl>[C:4]1(=[O:15])[N:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])[C:1](=[O:20])[C:2]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:3]12
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-Butyl phthalimidooxyacetate (compound 8) (0.5 g, 1.8 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.5 mL) was added, as illustrated in FIG. 6. The mixture was stirred at RT for one hour and evaporated to dryness. The residue was azeotroped with chloroform (3 times) to yield a white solid weighing 0.393 g (100% yield). The compound was characterized by NMR and MS as follows: 1) C-NMR (d-DMSO): 73.73, 124.13, 129.43, 135.65, 163.46, 168.87 ppm; and 2) H-NMR (d-DMSO): 4.76 (s, 2H); 7.86 (s, 4H) ppm; and 3) MS (ESI): 220.0 [M−H]−, 463.1 [2M-2H+Na]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15]O)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C([N:19](CC)CC)C.CS([Cl:28])(=O)=O.[N-]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O.O>[ClH:28].[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][NH2:19])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(CO)cc2s1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(CN)cc2s1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.52 g, 10.7 mmol) and triethylamine (3.00 mL, 21.5 mmol) in anhydrous THF (80 mL) at 0° C. was added methanesulfonyl chloride (1.24 mL, 16.0 mmol). The resulting mixture was allowed to stir at 0° C. for 30 min, diluted with EtOAc (400 mL), washed with saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was dissolved in anhydrous DMF (60 mL). After sodium azide (1.41 g, 21.6 mmol) was added, the mixture was heated at 50° C. for 30 min. After cooling to rt, the mixture was diluted with EtOAc (300 mL) and water (60 mL). The organic layer was further washed with water and brine, and then dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was dissolved in THF (60 mL) and water (6 mL). Triphenylphosphine (3.64 g, 13.9 mmol) was added and the mixture was allowed to stir at rt overnight and then concentrated. The residue was dissolved in ether (400 mL) and 4M HCl in dioxane (6 mL) was added dropwise. The solid formed was washed with ether (5×30 mL) and dried to give 6-aminomethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester, hydrochloride salt as a pale solid. 1H NMR (DMSO-d6, 200 MHz) δ 8.66 (brs, 2H), 8.24-8.10 (m, 2H), 8.06 (d, J=8.6 Hz, 1H), 7.62 (dd, J=8.4, 1.6 Hz, 1H), 4.34 (q, J=7.4 Hz, 2H), 4.13 (s, 2H), 1.32 (t, J=7.0 Hz, 3H). MS (EI): cal'd 236.1 (MH+), exp 236.1 (MH+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:32][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[O:23][CH:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)[C:9]=2[C:8]=1[CH3:33])=[O:6]>C1COCC1.CO>[F:31][C:27]1([F:30])[CH2:28][CH2:29][CH:24]([O:23][C:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=2[NH:15][C:14]2[C:9]3[C:8]([CH3:33])=[C:7]([C:5]([OH:6])=[O:4])[S:32][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:25][CH2:26]1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(F)(F)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.620 ml sodium hydroxide solution (2M) was added to 0.110 g 4-[2-(4,4-difluoro-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (cpd. 33.1) in 4 ml THF/MeOH (1/1). An additional aliquot of sodium hydroxide solution was added when the reaction mixture was stirred at rt overnight. After further 6 hours at rt the mixture was concentrated, the resulting aq. layer was adjusted to pH 4-5 with aq. 2 M aq.HCl and stirred under cooling for 30 minutes. Then the mixture was filtered, the filtercake was washed with water and dried.
Reaction SMILES: [CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(OCC)C)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]=[O:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:45](O)[CH2:46][OH:47].C([O-])(O)=O.[Na+].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:5]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:8]2=[N:9][C:10]([CH:19]3[O:20][CH2:45][CH2:46][O:47]3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCO
Reactant: CCCCc1nc2cc(-c3ccccc3)c(C=O)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCc1nc2cc(-c3ccccc3)c(C3OCCO3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 84.9 %

Procedure:
0.1 g(0.000169 mole) of the aldehyde compound obtained in step 11 of Example 1 and 0.032 g(0.000507 mole) of ethylene glycol were dissolved in 5 ml of benzene and to the resulting solution was added 0.01 mg of p-toluenesulfonic acid. The resultant was refluxed for 6 hours and thereto were added 1 ml of aqueous saturated NaHCO3 solution and 5 ml of water. The reaction solution was extracted with ethyl acetate(5 ml×3) and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resultant was recrystallized from hexane-methylene chloride to obtain 80 mg of the title compound(yield 85%).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])O.[Na+].[CH2:18]([O:20][CH2:21]C)C>>[CH3:18][O:20][CH:21]=[C:12]([CH2:2][CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3])[CH:13]=[O:16]
Reactant: O=C([O-])O
Reactant: CCOCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: C=CCCCCC(C=O)=COC

Procedure:
A mixture of 3.77 g of crude (5-hexenyl)malon-tetraacetal, 0.35 ml of water and 15 mg of p-toluene-sulphonic acid is heated to 80°-85° C. for 3 hours while stirring. After cooling the mixture is treated with 160 mg of sodium hydrogen carbonate and stirred for 1.5 hours. Subsequently, the reaction mixture is diluted with diethyl ether, extracted three times with cold 3N sodium hydroxide solution, washed with water and dried. The crude 3-methoxy-2-(5-hexenyl)acrolein which is obtained after evaporation of the solvent is further processed without additional purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[CH:10]1[C:15](O)=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].[CH2:18](Cl)CCl>>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[C:6]2[C:11]([CH3:10])([CH3:17])[CH2:12][CH2:13][C:14]([CH3:15])([CH3:18])[C:7]=2[CH:8]=1)[CH3:2]
Reactant: CCc1cccc(O)c1
Reactant: ClCCCl
Reactant: Cc1cccc(O)c1
Product: CCc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Yield: 66 %

Procedure:
Employing procedures and materials similar to those described in Example 1, except that 3-ethylphenol was substituted for m-cresol, and the reaction was carried out in the presence of ethylene dichloride as solvent, there was obtained the desired product, 3-ethyl-1-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene 66% theor., GLC purity 99%+, exhibiting the expected spectral data.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H](CO)O)O)O>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
reacting a feed liquor containing about 20 to 65% (w/w dry substance) glucose with a substantially purified xylose isomerase which is derived from Thermotoga maritima or Thermotoga neapolitana at a temperature of from 50° to 80° C., a pH of from 6 and 8 and a reaction time of from 10 minutes to about 5 hours, to produce a high fructose syrup containing from about 40 to about 50% fructose; and
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(Cl)(Cl)Cl
Product: O=C(Cl)c1ccccc1C(Cl)(Cl)Cl

Procedure:
Similarly, reaction of 2-trichloromethylbenzoic-acid with thionyl chloride affords 2-trichloromethylbenzoyl-chloride, which, on reaction with diethylamine, affords 2-trichloromethyl-N,N-diethylbenzamide. Following a procedure similar to that described in Preparation 5, reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxyl-amine-O-sulfonate affords 2-trichloromethyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-trichloromethylsaccharin.
Reaction SMILES: C[C:2]1[C:3]([CH:13]2[CH2:16][N:15]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:14]2)=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1>N1C=CC=CC=1.C(Cl)Cl>[F:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH:23][C:24]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]3[C:27]([CH:28]4[CH2:38][CH:29]4[CH2:30][O:31]3)=[CH:26][CH:25]=2)(=[O:10])=[O:11])=[C:3]([CH:13]2[CH2:14][N:15]([C:17](=[O:22])[C:18]([F:20])([F:19])[F:21])[CH2:16]2)[CH:2]=1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: Cc1c(F)ccc(S(=O)(=O)Cl)c1C1CN(C(=O)C(F)(F)F)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CN(C(=O)C(F)(F)F)C2)ccc2c1OCC1CC21
Reaction time: 18 h
Yield: 104.2 %

Procedure:
A solution of methyl 4-fluoro-2-[1-(2,2,2-trifluoroacetyl)azetidin-3-yl]benzenesulfonyl chloride (Intermediate 89, 0.192 g) and methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 42, 0.122 g) in pyridine (1 mL) and DCM (3 mL) was left to stand at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give methyl (1aRS,7bSR)-5-{4-fluoro-2-[1-(2,2,2-trifluoro-acetyl)azetidin-3-yl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.294 g) as a colourless gum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Reaction time: 24 h
Yield: 97.8 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperidin-4-one (1 g, 5 mmol), 4-fluoroaniline (0.56 g, 5 mmol) and acetic acid (0.286 ml, 5 mmol) in 1,2-dichloroethane (30 ml) was stirred at room temperature for 24 h. Sodium (triacetoxy)borohydride (1.48 g, 7 mmol) was then added and stirring continued for 24 h. The reaction mixture was washed with water, dried (MgSO4) and then concentrated in vacuo to give the title compound as a solid (1.44 g). δH (CDCl3) 1.30 (2H, m), 1.46 (9H, s), 2.02 (2H, m), 2.91 (2H, m), 3.35 (1H, m), 4.04 (2H, m), 6.54 (2H, dd), 6.88 (2H, t).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([N:16]([CH3:15])[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:5]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)ccc1F
Reaction time: 8 h

Procedure:
2-Fluoro-5-trifluoromethylbenzoyl chloride (80 mg, 0.35 mmol, CAS RN 207981-46-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (35 mg, 0.18 mmol, example 1, intermediate a) and DIPEA (92 μL, 0.53 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (36 mg, 53%). MS (ESI): m/z=389.0 [M+H]+.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.COC(OC)OC.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: COC(OC)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Yield: 99.3 %

Procedure:
0.182 g (1.00 mmol) of biphenyl-4-carbaldehyde and 0.224 g (1.20 mmol) tert-butyl piperazine-1-carboxylate were dissolved in 10 mL dry DCM. 0.35 mL (3.0 mmol) of trimethylorthoformate and 0.21 mL (1.50 mmol) triethylamine were then added to the reaction mixture at room temperature for 1 hr. The reaction was quenched with a solution of NaHCO3 and diluted with EtOAc. The layers were separated and the aqueous solution extracted with EtOAc 2×. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo to give 0.35 g (100%) of 51 which was used as is for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[CH3:32][Li].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:26]([OH:31])([C:27]([CH3:28])([CH3:30])[CH3:29])[CH3:32]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)C(C)(C)C)c2)cc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(C)(O)C(C)(C)C)c2)cc1
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, to a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)-2,2-dimethylpropan-1-one (275 mg) in THF (5 mL) was added a solution (1.1 M, 1.7 mL) of methyllithium in diethyl ether at −78° C., and the mixture was stirred for 16 hr while allowing the temperature to gradually rise to room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (182 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=[O:8].C(O[CH:13](OCC)[CH:14]([CH3:22])[CH:15](OCC)OCC)C.Cl>>[CH3:22][C:14]1[CH:13]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:15]=1
Reactant: CCOC(OCC)C(C)C(OCC)OCC
Reactant: Nc1[nH]ncc1C(=O)O
Agent: Cl
Product: Cc1cnc2c(C(=O)O)cnn2c1
Temperature: 95 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
A suspension of 5-amino-1H-pyrazole-4-carboxylic acid (271 mg, 2.1 mmol) and 1,1,3,3-tetraethoxy-2-methyl-propane (prepared accordingly to the procedure described in JACS126(7), 2004, 2194) (0.5 g, 2.1 mmol) in an aqueous solution of hydrochloric acid (6 M, 1.3 mL) was heated at 95° C. in a sealed tube. The solid material completely dissolved when the temperature reached 82° C. and then a solid precipitate crushed out of solution, stirring was continued for 5 minutes. The resulting mixture was cooled to room temperature and the solid was collected by filtration, rinsed with water and dried in vacuum oven to afford 305.1 mg (81% yield) of 6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=O.[OH-:11].[Na+].Cl.[NH2:14]O>C(O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[N:14][OH:11]
Reactant: [OH-]
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1c(Cl)cncc1Cl
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 90.5 %

Procedure:
To a suspension of 3,5-dichloro-4-pyridinecarbaldehyde (6.50 g, 36.9 mmol) in ethanol (55 mL) was added a solution of sodium hydroxide (1.77 g, 44.3 mmol) and hydroxylamine hydrochloride (3.08 g, 44.3 mmol) in water (30 mL). The suspension was heated to 90° C. The mixture was stirred at 90° C. for approximately 6.5 hours and then concentrated. Water was added and the resulting solid was isolated by filtration and dried under a nitrogen stream at 45° C. over phosphorus pentoxide to afford 3,5-dichloro-4-pyridinecarbaldehyde oxime (6.38 g, 33.4 mmol, 91%). 1H-NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.68 (s, 2H), 8.24 (s, 1H).